Update on new antiretrovirals for children and adolescents
Polly Clayden, HIV i-Base
There have been several recent FDA approvals for children in various age groups [1, 2, 3] and supporting data used to obtain these were shown in Washington at either the 19th International AIDS Conference (IAC) or the 4th International Workshop on HIV Pediatrics.
Additionally data from the adolescent cohort of the investigational antiretroviral dolutegravir were presented.
Dolutegravir is a promising new integrase inhibitor currently in phase 3 of development; results from SPRING-2, also at 19th IAC, showed it to be non-inferior to raltegravir at 48-weeks. 
Rohan Hazra presented the first paediatric data for DTG on behalf of the IMPAACT P1093 Study Team. 
IMPAACT P1093, is an ongoing, phase 1/2 multicentre, open-label pharmacokinetics (PK), safety dose finding, non comparative study of DTG plus optimised background regimen (OBR) in treatment experienced adolescents, children and infants >6 weeks of age, conducted in de-escalated age bands.
The paediatric doses selected will be those providing comparable PK exposure to the adult dose of 50mg, with AUC0-24 as the primary endpoint and C24 as the secondary endpoint. Protocol defined targets are: AUC 0-24, range of 37-67 ug*h/mL and C24, range 0.77 – 2.26 ug/mL. The study is looking at short and long-term tolerability and evaluates steady state PK of DTG given with OBR.
The first cohort enrolled 10 adolescents >12 to <18 years of a median age of 13.5 years. The majority (70%) were girls and overall the cohort had median time on ART of 12.8 years. Their median baseline CD4 percentage and viral load were 21.5% (IQR18.4-26) and 4.40 log copies/mL (IQR 4.17-4.84), respectively.
DTG was given at approximately 1 mg/kg once daily. The majority (90%) of the cohort weighed 40 kg or more and received the 50 mg adult tablet. Two reduced strength tablets of 25 mg and 10 mg have been developed to facilitate weight band dosing in older children. The remaining participant received 35 mg once daily (one 25 mg and one 10 mg tablet).
Intensive 24 hour PK evaluation was performed, following observed dose (days 5-10), after DTG was either added to a stable, failing regimen or started as monotherapy among those not currently taking ART. Background treatment was optimised immediately after completing the intensive PK.
Dr Hazra reported, in this cohort, target DTG exposure for both AUC0-24 and C24 was achieved. He noted there was moderate variability. The geometric mean (CV%) AUC0-24 and C24 were 46.0 (43%) ug*h/mL and 0.90 (58%) ug/mL, respectively.
At four weeks 70% (95% CI 34.7 – 93.3) of the cohort achieved viral load < 40 copies/mL and 90% (95% CI 55.5 – 99.8) <400 copies/mL; all the participants achieved at least 1 log10 drop or <400 copies/mL. The median change from baseline was 2.8 log copies/mL (95% CI 3.1 – 2.6). DTG was generally well tolerated, with one Grade 3 and no Grade 4 AEs, no treatment discontinuations due to AEs and no trends in laboratory abnormalities.
Dr Hazra concluded that these results support the dose selection in this cohort and the enrollment of a further 12 participants. Enrollment for the next cohort in children age 6 to <12 years has now begun and the development of a granule formulation for the younger children and infants is underway. 
In December 2011, the FDA approved a 100 mg scored chewable tablet and a 25 mg chewable tablet of raltegravir, and dosing recommendations for children 2 to 18 years of age and weighing at least 10 kg. 
IMPAACT P1066 is an ongoing phase 1/2 open label, multicentre trial to evaluate PK, safety, tolerability, and efficacy of multiple RAL formulations in treatment experienced adolescents, children and infants (those <2 years may have only failed PMTCT).
Sharon Nachman from the P1066 group presented 24 and 48 week results from 96 participants age 2 to 18 years receiving 400 mg twice daily of RAL adult film-coated tablet (6-18 years) and weight-based dosing (approximately 6mg/kg twice daily) of RAL orange banana flavour chewable tablet (2 to <12 years).  Dose selection was based on intensive PK data and RAL was given with an OBR. Children <2 years are given oral granules for suspension and this evaluation is ongoing. 
Adolescents and children were stratified sequentially in 3 age cohorts (I, 12 to18 years; II, 6 to <12 years; III, 2 to <6 years); the oldest group – cohort I – enrolled first. Safety was assessed through week 48. The primary virologic endpoint was viral load <400 copies/mL or >1 log reduction. Secondary endpoints were viral load <50 copies/mL, and change in CD4 percentage.
At baseline, participants were a median of 13 years with a median CD4 count of 481 cells/mm3 (1087 cells/mm3 in cohort III, n=20) and a mean viral load of 4.3 log copies/mL. Approximately half were girls and most were NNRTI or PI experienced, 78% and 83% respectively.
At 48 weeks, overall 78.9% of participants achieved viral load <400 copies/mL and 56.7% <50 copies/mL, with mean CD4 increase from baseline 155.7 (4.6%) cells/mm3.
Dr Nachman reported, 15 participants had Grade 3 and above clinical AEs, including one with drug related psychomotor hyperactivity, abnormal behavior and insomnia; 16 participants had Grade 3 and above laboratory AEs including one with drug related AST and ALT; 14 participants had serious clinical AEs including one with drug related rash and two participants with serious laboratory AEs including one with drug related increased transaminase. There were no discontinuations due to AEs and no deaths.
She noted that these data were used to obtain US approval in the 2 to <10 years age group. Table 1 shows recommended doses for the chewable tablets based on approximately 6mg/kg twice daily. The 100 mg tablet is scored and so can be divided in half.
|Weight kg||Dose mg twice daily||Tablets (number / size mg)|
|10 to <14||75||3 x 25|
|14 to <20||100||1 x 100|
|20 to <28||150||1.5 x 100|
|28 to <40||200||2 x 100|
|>40||300||3 x 100|
The FDA also recently approved etravirine (ETR) scored 25 mg tablets and dosing recommendations for treatment experienced children and adolescents 6 to 18 years, weighing at least 16 kg, in March 2012.
Gareth Tudor-Williams presented data from the PIANO study used to obtain this approval.
PIANO (TMC125-C213) is a 48-week, phase 2, open-label trial of the safety, efficacy and PK of ETR 5.2mg/kg (maximum dose 200mg) twice daily in treatment-experienced children and adolescents 6 to 18 years of age, given with OBR.
Overall 101 participants enrolled the in study, of which, 41 were children (6 to 12 years) and 60 adolescents (12 to 18 years); 63% were girls. Their median age at baseline was 12 years; their viral load 3.9 log10 copies/mL and CD4 count 385 cells/mm3. The majority (75%) was NNRTI experienced. Of those enrolled 75% completed the trial.
Most discontinuations were associated with AEs or non-adherence, both 8%.
Regardless of severity or cause 27% of participants had an upper respiratory tract infection and 23% rash. Rash was at least possibly related to ETR and grade 2 or more AEs in 13% of participants. Four percent discontinued due to rash.
Serious AEs were observed in 5% of participants while 14% experienced a grade 3/4 AE. Grade 3 or 4 treatment-emergent laboratory abnormalities were observed in 10%.
At 48 weeks, by intent to treat (non-completer equals failure) analysis, overall 67% and 56% achieved viral load of <400 copies/mL and <50 copies/mL respectively. Although the study was not powered to make statistical comparisons between children and adolescents, the younger age group appeared to have better responses: these proportions were 76% vs 68% and 62% vs 48% in children and adolescents respectively. The median time to <50 copies/mL was 16 weeks for children and 24 weeks for adolescents.
The mean change in CD4 count from baseline was 156 cells/mm3 overall, 178 cells/mm3 in children and 141 cells/mm3 in adolescents.
Adherence was measured by pill count and self reported questionnaire; self reported adherence was higher than that estimated by pill count. At 48 weeks, 65% of participants were adherent according to the results of the questionnaire. When evaluated by pill count, 39% (46% of children, 35% of adolescents) were >95% adherent; 70% were >80% adherent.
Overall 41% of participants were classed as virologic failures, this proportion was 50% of adolescents and 27% of children. Of these 29% were non-responders and 12% rebounders.
Of 30 with endpoint genotype data, 18 had NNRTI resistance-associated mutations. The most mutations were: Y181C (n=8), E138A (n=3), L100I (n=3) and/or V90I (n=3).
Dr Tudor Williams noted that the better responses observed in children than adolescents, were most likely due to less advanced disease, better adherence and less previous NNRTI use prior to treatment with ETR.
An oral suspension of fosamprenavir/ritonavir (FPV/r) was also approved in the US earlier this year in April for use in children 4 weeks to less than 6 years of age.
Jorg Sievers presented data from the APV20002 study that looked at PK, safety and antiviral activity of FPV/r twice daily in PI-naive and PI-experienced children 4 weeks to <2 years of age. This evaluation was across two age cohorts: cohort 1, 6 months to <2 years and cohort 2, 4 weeks to <6 months of age.
APV20002 was a phase 2, open label, multicentre study in which Intensive pharmacokinetic sampling was performed at 2 or 8 weeks and pre-dose samples were collected every 4-12 weeks. Safety and viral load were monitored every 4-12 weeks.
The older cohort was dosed at 45/7 mg/kg FPV/r twice daily and the younger 45/10 mg/kg twice daily.
Overall 54 children were included in the intent-to-treat-exposed analysis (28 in cohort 1 and 26 in cohort 2). At baseline the children were a median age of 6 months (range 2 – 24), with a median viral load of 5.6 log10 copies/mL (range 5 – 6.15) and CD4 percentage of 26% (range 18 – 34).
At 48 weeks, the median exposure to FPV/r was 640 days (range 8-1093), with 78% exposed >48 weeks and 50% >96 weeks.
When the investigators compared plasma amprenavir (APV) AUC0-t to historical adult data, the geometric mean ratios were 0.744 (90% CI 0.542 – 0.957) and 0.720 (90% CI 0.568 – 0.975) in cohort 1 and 2 respectively. For the Ct these values were, 1.00 (90% CI 0.833 – 1.21) and 0.397 90.298 – 0.528).
Despite lower Ct in the younger cohort, antiviral response was similar across the age groups: 64% percent of children in cohort 1 and 58% in cohort 2 achieved viral load < 50 copies/mL at 48 weeks. The median increase in CD4 percentage was 5% in both cohorts.
The most common AEs were diarrhoea (54%), gastroenteritis (36%) and upper respiratory tract infection (36%). Drug-related grade 2-4 AEs occurred in 20% of children, most frequently increased blood chlolesterol (10%) and gastroenteritis (3%). Twenty-two children experienced serious AEs, three were considered to be drug-related. Three children died following serious AEs including one two month old boy with traditional (herbal) medicine poisoning.
Although somewhat opaque in their approach, the EMA are expected to follow suit with these approvals in the not too distant future. More details on these drugs and others under investigation for children can be read in our paediatric antiretroviral pipeline report:
- Food and Drug Administration (U.S.). Isentress (raltegravir): pediatric dosing recommendations and 2 chewable tablet formulations for pediatric dosing. 21 December 2011.
- Food and Drug Administration (U.S.). Intelence (etravirine): pediatric dosing recommendations and new scored 25 mg tablet for pediatric dosing. 26 March 2012.
- Food and Drug Administration (U.S.). New pediatric Lexiva dosing regimen for patients from at least 4 weeks to less than 6 years of age. 27 April 2012.
- Raffi F et al. Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral-naive adults: 48 week results from SPRING-2 (ING113086). 19th International AIDS Conference. 22-27 July. Washington DC. Oral abstract THLBB04.
- Hazra R et al. Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093. 19th International AIDS Conference. 22-27 July 2012, Washington. Oral abstract TUAB0203.
- Nachman S et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through week 48. 19th International AIDS Conference. 22-27 July 2012, Washington. Oral Abstract TUAB0205.
- Tudor-Williams G et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents: PIANO 48-week results. 19th International AIDS Conference. 22-27 July 2012, Washington. Oral abstract TUAB0204.
- Sievers J et al. Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir-containing regimens in HIV-positive four weeks to < two year-old children (48-week data, study APV20002, a prospective, open-label, multi-centre, 48-week cohort study). 19th International AIDS Conference. 22-27 July 2012, Washington. Oral abstract TUAB0202.