Both the 5th paediatric workshop and the 7th IAS conference had excellent presentations on pipeline antiretrovirals, dosing strategies and formulations.
Some of the studies made an appearance at both meetings -- as oral or poster presentations -- as co-submission was encouraged. The IAS session "Expanding ARV options for children: first line and beyond" was webcast.1
This report combines presentations from both meetings.
Atazanavir (ATV) powder boosted with ritonavir (RTV) liquid once daily plus optimised dual NRTI background therapy is effective in ART-naive or experienced children aged 3 months to 6 years with no additional safety issues to previous ATV paediatric and adult studies.2,3
Atazanavir is currently approved for children aged 6 years and above. PRINCE 1 is an ongoing phase 3b prospective, international, multicentre, open label, two-stage clinical trial -- 48-week data were presented. This trial has been ongoing since 2010
The study enrolled ART-naive or -experienced (without prior ATV use) children with viral load >1000 copies/mL. There were two dosing regimens: stage 1 -- ATV powder boosted with RTV liquid, based on 3 weight bands (see dosing table 1) and stage 2 -- switch to ATV capsules after 48 weeks on ATV powder or when they reached 6 years or >25 kg. Stage 1 efficacy and safety were presented.
A total of 56 children were enrolled, 46 completed stage 1, and 45 made the transition to stage 2. The majority (68%) of children were from Africa. At baseline, they were a median age of 28.5 months (range 3 to 65), with mean viral load and CD4 counts of 4.62 log10 copies/mL and 1192.6 cells/mm3; 61% were ART-naive.
Using modified intent-to-treat analysis, at week 48, 33 (61%) children had viral load <50 copies/mL, and 40 (74%) had viral load <400 copies/mL. Viral suppression increased with higher weight: 48% in the 5 to <10 kg compared to 71% in the 15 to < 25kg weight band had viral load <50 copies/mL.
There was no significant difference between ART-experienced and -naive children in rate of viral suppression, with 60% and 62% <50 copies/mL respectively. Mean CD4 count change from baseline was 397 cells/mm3, respectively 550, 225 and 374 cells/mm3 in the increasing weight bands.
By week 48, 14 children had virological failure, 57% were ART-naive and 43% ART-experienced. Nine had paired genotypic data (baseline and on treatment) and 6 paired phenotypic. This showed no acquired phenotypic resistance to ATV, ATV/RTV or any NRTI or NNRTI. One child developed phenotypic resistance to saquinavir. No child developed any major PI substitution to ATV or ATV/RTV.
There were no new or unexpected safety events and no deaths. Eleven children (20%) had on treatment SAEs. Five children (9%) discontinued due to AEs, 4 were in the 5 to <10 kg group. Seven (13%) had hyperbilirubinaemia-related AEs and 3 cardiac disorders, 2 were considered related to the study treatment.
Through 48 weeks on ATV powder, common AEs occurred in 52 children (93%); the most frequent being upper respiratory tract infections (36%), diarrhea (36%) and vomiting (29%).
The PRINCE 2 study of ATV powder in 3 months to <11 in 95 children years is ongoing. A PK, safety and efficacy analysis of the combined data sets will be conducted.
Darunavir/ritonavir (DRV/r) plus an optimised background regimen was effective in treatment-experienced children, with no new safety concerns compared to adults at 48-weeks in the ARIEL trial.4
The primary 24-week analysis from this phase 2, multicentre, international trial led to the approval of DRV/r for treatment experienced children aged 3 to <6 weighing at least 10 kg.
Children enrolled in ARIEL had been on ART for 12 weeks or more with viral load >1000 copies/mL and less than three darunavir-associated mutations.
They initially received DRV oral suspension at 100mg/mL plus RTV 20/3mg/kg twice daily with an optimised background regimen. Following pharmacokinetic (PK) analysis after two weeks of receiving this dosing regimen and Data and Safety Monitoring Board recommendations, children weighing <15 kg and 15 to < 20kg were given DRV/r 25/3mg/kg and 375/50mg twice-daily respectively.
The 48-week analysis included 21 children with a median age of 4.4 years (range 3-6) at enrollment. Their mean baseline viral load was 4.34 copies/mL, median CD4 count 927 cells/mm3 and CD4 percentage 27.7%.
The majority of the children received two background NRTIs and two children received three NRTIs.
At week 48, 81.0% of children had viral load <50 copies/mL and 85.7% <400 copies/mL (ITT-TLOVR). Notably at 24 weeks only 57.1% of children had achieved virological suppression <50 copies/mL but 81.0% were <400 copies/mL.
Two children with baseline DRV mutations (L33FL and L76V) had viral load <50 copies/mL at 24 and 48 weeks. There were 3 virologic failures at week 48 (2 never suppressed; 1 rebounder); of the 2 with paired baseline/endpoint genotypes, neither developed PI nor NRTI mutations. Both remained susceptible to DRV and other NRTIs in the background regimen.
There was one AE possibly related to DRV (ECG QT prolongation), and one discontinuation due to grade 2 vomiting probably related to RTV. Two children had grade 4 AEs (stenosing tenosynovitis and asthmatic crisis), both considered serious but not related to the study treatment. All laboratory abnormalities were grade 1 except for one grade 3 neutropenia, which had been present at baseline and was not considered treatment-related.
A small Thai pilot study looked at PK and efficacy of once daily compared to twice daily dosing of DRV/r in older children and adolescents.5
Treatment-experienced children and adolescents receiving DRV/r twice daily in optimised regimens, with no prior DRV-associated mutations, and virologically suppressed (<400 copies/mL) for at least 6 months were enrolled.
Twelve-hour blood sampling (pre-dose and 2, 4, 6, 8 and 12 hours post-dose) for PK was performed at enrollment. DRV/r was then switched to once daily dosing and 24 hour sampling (as previously but with 18 and 24 hours post dose) was repeated 2 weeks later. Twice daily DRV/r doses of 375/100, 450/100, and 600/100 mg were increased to once daily doses of 450/100, 600/100, and 900/100 mg, respectively.
DRV/r PK parameters were calculated using non-compartmental analysis. CD4 counts and viral load were measured at baseline and at 12, 24, 36 and 48 weeks.
Eight children and adolescents with a median age of 16 years (range 11.0-18.9) were evaluated. Their median CD4 count was 806 cells/mm3 (range 621-1200). DRV AUC0-24h with twice daily and once daily dosing was 59.6 (range 38.5-139.3) and 51.5 (range 20.7-117.7) mcg.hr/mL, respectively. The C12h and C24h DRV concentrations were 1.4 (range 0.7-4.9) and 0.7 (range 0.2-2.4) mg/L, respectively.
PK parameters for RTV were: AUC0-24h with twice daily and once daily dosing 8.8 (range 3.3-11.1) and 6.9 (range 0.7-9.3) mcg.hr/mL, p=0.95; C12h and C24h 0.33 (range 0.2-0.5) and 0.08 (range 0.03-0.12) mg/L, respectively, p<0.001.
All children had DRV concentrations above the IC50 for wild type virus (0.055 mcg/mL) while receiving either once or twice daily dosing.
Six of eight children had viral load <50 copies/mL at all tests during the 48 weeks.
Maraviroc (MVC) is a CCR5 antagonist, approved to treat adults and adolescents aged 16 years or more with CCR5-tropic HIV but not yet approved for paediatric use.
Data were presented from 94 participants in the ongoing A4001031 study in treatment-experienced children and adolescents aged 2 to <18 years.6
This is an open-label, two-stage (stage 1: dose-finding; stage 2: safety/efficacy), age-stratified, non-comparative, multicentre study to evaluate the safety, tolerability, and PK of MVC plus optimised background therapy.
Participants are enrolled into one of four cohorts by age and formulation: cohort 1, >2 to <6 years/liquid (n=13); cohort 2, >6 to <12 years/tablet (n=27); cohort 3, > 6 to 12 years/liquid (n=12), and cohort 4, > 12/tablet (n=42).
Those eligible have viral load >1000 copies/mL, on stable or no therapy and have experienced >6 months in at least two ARV classes.
Dosing is complex and determined by body-surface area (BSA) and concomitant medications. Dose adjustment occurred if average concentrations were <100 ng/mL at Week 2. Doses ranged from 50-450 mg twice daily.
A total of 75/94 participants were followed for 48 weeks. At the time of analysis 49 were still on treatment and 26 discontinued MVC, 14 with virological failure and evidence of non-adherence -- which was more frequent in adolescents -- and 3 participants with virological failure had tropism shift. Of those remaining on treatment, 52% and 40% had viral load <400 and 50 copies/mL respectively.
AEs occurred in 60 (63%) participants and 10 (10.6%) were grade 3 or 4. There were no deaths and 3 discontinuations due to AEs. Most common (>10%) AEs were: infection and infestations (49%), gastrointestinal disorders (36%), nervous system disorders (14%), reproductive system and breast disorders (13%), and skin and subcutaneous tissue disorders (12%).
MVC PK from this study was presented separately.7 This sub study using PK profiles from 51 participants found BSA-based dosing with CYP3A4 inhibitors scaled from the 300 mg adult dose provides MVC exposures achieving the target Cavg >100 ng/mL in all cohorts.
Non-inhibitor ART regimens are still under evaluation and PK data suggests that doses are likely to be higher than the initial adult BSA scaled dose.
Enrollment in A4001031 will continue out to five years.
Efavirenz (EFV) plus NRTI backbone combination is the preferred WHO first line antiretroviral therapy for HIV-positive children more than 3 years and weighing above 10 kg.
WHO weight band dosing reduces the proportion of children with EFV concentrations below target compared to FDA, but this is achieved with a higher proportion having concentrations above target and in turn a higher risk of toxicity, according to a study comparing the two dosing guidelines using a population PK approach.8 See Table 2.
|Table 2: Efavirenz Dosing Guidelines|
|200 mg||10 to <15 kg||10 to <14kg|
|250 mg||15 to <20 kg||14 to <25|
|300 mg||20 to <25 kg|
|350 mg||25 to <30 kg||25 to <35|
|400 mg||30 to 40 kg|
|600 mg||> 40 kg||> 35 kg|
* The study used 2010 dosing guidance -- this is unchanged in the 2013 revision.
This analysis included EFV plasma concentration data from 190 children (623 plasma samples); 40 had 24-hour PK sampling data available. EFV was given according to FDA weight band recommendations. Population PK was estimated using nonlinear mixed effects modelling.
Median age was 7.2 years (0.1* to 12.2), bodyweight 16 kg (5 to 42), and efavirenz dose 300 mg (200-600). *The investigators noted that this child at the lowest end of the range first received dual NRTI before starting EFV at 5.4 years.
A one-compartment PK model was used with delay absorption. Weight influenced EFV apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability.
The estimated median AUC0-24 was 49 mg/L.hr (8 to 296). A predicted EFV C12 was 2.3 mg/L (0.07 to 11.9). Of 190 children, 16 (8%) had predicted EFV C12 below 1 mg/L (subtherapeutic range) and 12 (6%) above 4 mg/L (toxic range) with FDA dosing. No serious adverse events were reported.
Simulations predicted similar proportions of children with C12 between 1 mg/L and 4 mg/L with both dosing guidelines. Proportions of children with C12 in the subtherapeutic range were reduced across all weight bands with WHO compared to FDA dosing, respectively: 8 vs 16%, 11 vs 14%, 12 vs 16% and 8 vs 15% in the 14 to <15 kg, 15 to <20 kg, 25 to 32.5 kg and 35 to 40 kg groups; but proportions in the toxic range increased, respectively: 39 vs 25%, 33 vs 24%, 28 vs 21% 42 vs 21%.
A previous study of Thai children an 11% frequency of CYP2B6 TT genotype (EFV concentration >6 mg/L), genotypes were not determined in this one but several children had EFV concentrations >6 mg/mL which could be explained by this phenomenon.
Safety data on EFV in children dosed according to the WHO weight bands are needed.
This was a multicentre, randomised, open-label trial conducted at 11 sites in Thailand. Children and adolescents aged < 18 years weighing 25-50 kg with viral load <50 copies/mL were randomly assigned to FDA -recommended standard dose or low dose of LPV/r.
LPV/r doses for children 25 to 35 kg were 300/75 mg or 200/50 mg, and >35 to 50 kg were 400/100 mg or 300/75 mg twice daily. The primary endpoint was the proportion of children with viral load <50 copies/mL at 48 weeks. Secondary endpoints were LPV Ctrough and the proportion of children with dyslipidemia.
The study enrolled 199 children, with mean age of 13.4 years (SD 2.2) years, and CD4 of 787 (319) cells/mm3; 98 were randomised to standard and 101 to the low dose arm. The NRTI backbones were AZT/3TC (47%), AZT/ddI (18%), TDF/3TC (16%) and others (20%).
Loss to follow up was 7 (3.5%) participants -- 3 in the standard and 4 in the low dose arms.
At 48 weeks, by intention to treat analysis, the proportions of participants with viral load <50 copies/mL were 91.8% in the standard and 88.1% in the low dose arms, difference -3.7% (95% CI -12.0 to 4.6%), p=0.38. Eight participants had viral load >400 copies and factors associated with this were poor adherence (aOR 3.3) and weight 35 to 50kg (aOR 3.6).
Median LPV Ctrough at week 48 were 6.9 (range 0.3. to 20.4) and 5.2 (0.2 to 11.8) mg/dL, standard and low dose respectively. Fourteen (7.3%) had Ctrough < 1 mg/dL (4 in standard and 10 in low dose arms, p = 0.1).
More children in the standard arm had cholesterol > 200 mg/dL (34.4 vs 20.6%, p=0.03) and triglyceride > 150 mg/dL (60.4 vs 44.3%, p =0.03) than those in the low dose arm.
ABC and 3TC are approved for once daily use in adolescents aged 12 and above and adults, but not yet in younger children.
Previous studies in European and African children found similar PK for once and twice daily ABC and 3TC.
This was a single-arm, open- label, crossover study, conducted in 30 Thai children and adolescents aged <18 years, weighing >14 kg, viral load <50 copies/mL, and HLA B5701 negative. ABC and 3TC daily doses by weight were 300 and 150 mg for 14 to <20 kg, 450 and 300 mg for 20 to <25 kg, and 600 and 300 mg for >25 kg.
The study used originator ABC and 3TC scored tablets. Intensive PK sampling was performed following14 days of each dose. GMR (90% CI) of AUC0-24 and Cmax were compared.
At baseline, participants were a median age 8.8 years (IQR 6.6-11.3) years, weight 21.9 kg (IQR 11.9-30.6) kg and CD4 count 841(IQR 580-1073) cells/mm3.
ABC and 3TC was given with EFV (60%), LPV/r (37%), or NVP (3%). No children had SAEs or laboratory abnormalities during the PK study.
GM of AUC0-24 for once and twice daily ABC were 14.43 and 10.65 mg·h/L, which gave a GMR 1.36, (90% CI 1.19-1.55). For 3TC, these values were 17.70 and 18.11 mg·h/L, GMR 0.98 (90% CI 0.84-1.14).
GMR of ABC Cmax for once and twice daily was 2.84 mg/L (90% 2.28-3.53); 3TC was 1.69 mg/L (1.35-2.09).
ABC AUC0-24 once daily was higher overall but lower in the 14 to 20 kg weight band. 3TC AUC0-24 once and twice daily was bioequivalent -- there was higher 3TC exposure in Thai children compared to historical data in children and adults but no toxicities were observed.
The study demonstrated the non-inferiority of once daily ABC and 3TC compared to twice daily and provides further support for this dosing regimen in children.
A generic dispersible fixed dose combination (FDC) of 3TC/NVP/AZT for children is bioequivalent to the originator liquids.11
Mylan (formerly Matrix) tested dissolution of 3TC/NVP/AZT 30/50/60 mg FDC tablets in 0.1N HCl /Type II/75 rpm/900mL media. Bioequivalence was tested in 48 healthy adults aged 18 to 50 under fasting conditions. Originator liquids were used as reference: Epivir solution, Viramune suspension and Retrovir syrup.
The tablet has a short disintegration time and disperses quickly in water -- after 10 minutes, 98 to 100 of the API was dissolved.
In the bioequivalence study all participants were randomised to receive a single dose of either the FDC or reference products during period 1 and then the other after a washout period of 21 days. Very intensive sampling was performed up to 72 hours. The relative bioequivalence is shown in table 3.
|Table 3: Relative Bioequivalence (% of Reference) of 3TC/NVP/AZT Tablets to Originator Liquids|
|3TC||105.51(95.49 -115.54)||98.42(90.69 -106.15)||98.59(91.15-106.03)|
|NVP||102.52(98.18 - 106.86)||100.55(99.07 - 102.04)||--|
|AZT||99.37(91.16 - 107.58)||101.12(97.83 - 104.41)||101.27(98.09-104.46)|
The study found the time/concentration curves for the dispersible tablet and the reference products were indistinguishable, demonstrating equal bioavailability.
Data from PRINCE 1 has taken its time -- adult ATV approval was in 2003 and for older children 2008. Presumably data from the combined sets from PRINCE 1 and 2 will eventually be submitted for approval. Whether there will be generic heat stable versions of ATV/r for children remains to be seen.
DRV/r might also be a good second line option for children over three who started on NNRTIs if suitable heat stable generics were available.
As with adults maraviroc will be far to complicated to use for all but a few treatment experienced children in rich countries.
According to this model, the risk of EFV toxicities seems quite high with WHO weight band dosing. This is not ideal particularly with double the proportion in the toxic range in the higher weight band, i.e., older children and adolescents who are most likely to receive it.
The Thai data for ABC and 3TC once daily reinforces that from ARROW and the PENTA studies. ViiV are submitting ARROW and PENTA data for a once daily indication for children (particularly with a view to producing a scaled down paediatric once daily FDC of dolutegravir plus these two NRTIs).
Finally, indisputable bioequivalency data for the only paediatric FDC recommended in the new WHO guidelines that is currently available.
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