Other promising pipeline drugs, such as the prodrug of tenofovir, GS 7340, and the stavudine derivative festinavir, need to be studied in children as soon as sufficient adult data are obtained.
Over 12 years after efavirenz was approved in adults, there is finally a smattering of data for its use in children under three years of age -- including TB-coinfected infants -- from IMPAACT P1070 and a couple of other investigator-led trials. Dosing difficulties with large variability remain. The bioavailability of the oral solution is less than 70% of that of the solid forms. High doses (i.e., large volumes of liquid) are needed to achieve adequate exposure in plasma.
This drug is important, as dosing with TB medications -- specifically rifampin (rifampicin) -- is complicated by boosted PIs and nevirapine. Whether there will be a suitable formulation of efavirenz with an indication for very young children remains to be seen.
|TABLE 5. The Innovator Pipeline
||Drug||Sponsor||Formulation||Comments||Atazanavir||BMS||Oral powder, 50mg sachet|
Capsule, 100mg, 150mg, 200mg, 300mg
|Ongoing phase II PACTG 1020A and PRINCE 1&2, treatment-naive and treatment-experienced with or without ritonavir, from 3 months to 6 years||Darunavir||Tibotec/Johnson & Johnson||Oral suspension, 100mg/1mL||ARIEL phase II -- filed with FDA/EMA for treatment-experienced, 3 to 6 years||Dolutegravir||Shionogi/ViiV||Older children: tablets, 10mg, 25mg, 50mg|
Younger children: to be decided.
|Phase I and II IMPAACT P1093, from 6 weeks to 18 years||Elvitagravir/cobicistat(booster)/Quad||Gilead||To be decided.|
Solid and liquid forms in development, separately and coformulated as Quad (solid tablet only)
|183-0152 EVG, treatment-experienced 12 to 18 years; integrated plans for pediatric studies under discussion||Etravirine||Tibotec/Johnson & Johnson||Dispersible tablets, 25mg (scored), 100mg||Ongoing phase II PIANO, treatment-experienced, 6 to 17 years|
Phase I and II IMPAACT P1090, treatment-naive/treatment-experienced, 2 months to 6 years, planned
|Maraviroc||Pfizer/ViiV||Oral suspension, 20mg/ml||Phase IV A4001031, treatment-experienced, CCR5-tropic, 2 to 12 years||Raltegravir||Merck||Chewable tablet, 25mg, 100mg|
Oral granules for suspension, 100mg sachet
|Phase II IMPAACT 1066, 4 weeks to 18 years; IMPAACT P1097, neonates||Rilpivirine||Tibotec/Johnson & Johnson||Oral granules, 2.5mg base/g||Phase II, TMC278-C220, planned 0-12 years||Tenofovir DF||Gilead||Oral powder, 40mg/g|
|Phase III, 104-0321 12 to 18 years; 104-0352, 2 to 12 years|
Various ongoing discussions have anticipated how paediatric treatment guidelines might look in 2013 and 2016. This will depend on the approval status of some of the pipeline drugs and the results of ongoing trials.
2013: Universal treatment of all young children is anticipated to extend from up to 24 months to up to 36 months (or possibly five years) old.
2016: Universal treatment of all children less than five years old.
Children aged five or older share the criteria for treatment initiation with adults. This is currently at a CD4 count of 350 cells/mm3 or lower, or at any CD4 count in the presence of active TB or hepatitis B.
The change will depend on the results of the INSIGHT START study 001. It is expected to mean starting at a CD4 count of 500 cells/mm3 or lower, or a higher threshold.31
2013: FDCs as much as possible and progressive phase-out of stavudine. Lopinavir/ritonavir-based treatment for all infants and children under three years of age regardless of NNRTI exposure.
2016: For all children under five years of age; either induction/maintenance of two NRTIs plus a boosted PI to achieve suppression and switch to rilpivirine to maintain suppression (this will depend on NEVEREST results) or two NNRTIs plus dolutegravir with or without switch.
2013: If lopinavir/ritonavir is used first, either NNRTI or darunavir (depending on approval -- possibly etravirine or raltegravir).
If NNRTI is used first-line, boosted PI as second-line.
NRTIs will depend on the status of tenofovir and what was used first-line. Didanosine will continue to be an option although its phase-out is anticipated.
2016: Induction/maintenance first-line would allow for reuse of boosted PI or douletegravir for second-line, even if these were part of the initial (induction) regimen.
If integrase inhibitors are available, then second-line will probably be a boosted PI plus one of these; if not, then a boosted PI. Hopefully atazanavir and darunavir will be available in appropriate formulations.
If cobicistat is available it may offer an alternative to ritonavir as booster.
2013: Two or three regimens of integrase inhibitors (raltegravir), newer boosted PIs (darunavir) and newer NNRTIs (etravirine).
2016: Unclear, but etravirine may be less useful if ripivirine is given as maintenance.
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