Though the large burden of TB among pediatric populations is widely recognized, children represent a historically understudied population in TB research. Given that efficacy trials in adult TB patients depend on production and culture of sputum samples during treatment and young children cannot produce sputum samples for testing, dosing recommendations for TB drugs for children are generally based on PK studies rather than efficacy trials. New compounds that have demonstrated efficacy for which a dose has been selected in adults should immediately be tested in children, beginning in adolescents, and then proceeding to progressively younger groups of children. The importance of this is illustrated by the example of INH and RMP. When given to children at the same
mg/kg dose as adults, concentrations are much lower, and children were treated with suboptimal doses of these drugs for decades. Only recently were the doses recommended by the World Health Organization increased to reflect these age-related differences in drug disposition [52
]. A pediatric dose finding study of bedaquiline among children with MDR-TB is under development by the NIAID-funded International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) network with support from Janssen. Similar dose finding studies are required for all of the new TB drugs in the pipeline as well as many currently existing TB drugs. Development of formulations that can be used in young children is a high priority for all promising investigational TB drugs.
The magnitude and variability of drug interactions may be expected to be different in pediatric populations than in adults, as expression of key metabolizing enzymes changes as children develop [53
], and responses to drugs that inhibit or induce metabolizing enzymes may also vary with age. Therefore, dose adjustments for ARVs when taken together with rifamycins do not necessarily follow from adult recommendations and should be tested specifically in children to ensure adequate drug exposures. For example, while double-dose ritonavir-boosted LPV may result in adequate LPV concentrations in adults taking RMP, the same is not true among children [25
]. Similarly, NVP concentrations in young children are substantially reduced by RMP coadministration [55
]. Determining the optimal doses of RTV and LPV to give children who are also taking RMP for TB remains a high priority, particularly among very young children for whom EFV dosing recommendations have not been established and is under active investigation [54
]. RBT is not available in a pediatric formulation, so substitution of RMP with RBT is not currently an option.
HIV/TB drug interactions in pregnant women and the impact of these interactions on prevention of mother-to-child transmission also deserve attention. Up to now, there have been no published data on the combined effects of pregnancy and RMP on ARV concentrations and efficacy of HIV treatment. For women with HIV and TB who cannot receive EFV because of potential teratogenic effects early in pregnancy and for whom NVP is contraindicated because of CD4 count higher than 250 cells/mm3, options are limited. The safety, PK, and efficacy of higher dose LPV/r or RAL when given with RMP-containing TB treatment have not been tested in pregnant women.