Pediatric Formulations of ARVs: Including an Exciting New Class
These data represent great strides in paediatric drug development and, if approved, these formulations will offer important treatment options for the youngest age group. Integrase inhibitors would mean a new therapeutic class for young children that might overcome some of the shortcomings of the currently available drugs. The sprinkle formulation of LPV/r, is now being studied in CHAPAS 2 and also as part of a programme by Drugs for Neglected Diseases initiative (DNDi) to come up with an affordable regimen appropriate for children under two.
Data to guide the dosing of children less 3 years for efavirenz (EFV), the preferred first line anchor drug for older children and adults, remains elusive. A poster at this meeting showed that CYP2B6 genotype strongly influences EFV PK and safety in this age group.  Aggressive dosing (~40 mg/kg) produced therapeutic EFV concentrations in most (68%) children less than 3 years with GG/GT genotype, however, this leads to excessive exposure in those with TT genotype. These data suggest that optimal use of EFV in children less than 3 years requires pretreatment genotyping, and the study protocol has been amended to include this at screening. A related poster showed data from model predicting the PK of EFV in children with different CYP2B6 genotypes, with simulations that indicate that genotype- guided dose optimisation could be used in paediatric patients.  Although EFV could be important for use in HIV/TB coinfected infants, complex genotype screening, the risk of resistance from NNRTI exposure in PMTCT and the probability that boosted PIs will be universally recommended in RLS make it an unlikely option in this age group.
For older children, Abbott has developed a low dose tablet of LPV/r (100/25 mg). Another paediatric PK poster showed data from a small study of 8 children aged 4.5 to 9 years designed to evaluate the comparability, efficacy, and tolerability in stable patients switching to this tablet from the oral solution.  PK analysis showed mean LPV AUC and Cmax ratios between liquid and tablet formulations to be 1.01 and 1.02, indicating that overall, the concentrations achieved with the different formulations were essentially the same.
And recently there have been some important FDA approvals including tenofovir and raltegravir for children two years of age and above and darunavir for those three years and above, which we reported in the February edition of HTB. [8, 2, 9] Also for etravirine for children of six and above, including a new scored 25 mg tablet for paediatric use (see later in this HTB). Paediatric approval from the EMA is awaited for these drugs and unlike the US tenofovir is not approved for the 12 to 18 years age group. For details see Table 3.
For RLS it is hoped that first line treatment for children above three can be aligned with adults and dosed according to weight bands with tenofovir/3TC/EFV using suitable FDCs. A further children's PK poster showed that tenofovir given in combination with 3TC/EFV achieved comparable plasma exposure to that achieved in adults.  The investigators also noted that concerns remain about bone and renal toxicities with this drug.
A final poster on paediatric PK reported from a study revealing lower than expected darunavir and etravirine concentrations when the two were given together to older children and adolescents 11 years of age and above.  The study highlights both the importance of studying drugs in combination -- to determine the contribution of drug-drug interactions -- and in different populations, in this case to determine whether the results are age-related. Whether these findings will affect clinical response requires further study.
Overall the data presented at CROI (and recent FDA approvals) shows promise for paediatric HIV treatment in the near future.
Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 58 March 2012, Seattle.
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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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