Last year both the FDA and the EMA approved tenofovir (TDF) for children two years and above, albeit with rather sparse data. The recommended dose is 8 mg/kg (up to a maximum of 300 mg), once daily using either an oral powder formulation or reduced strength tablets.
For adults, with FTC or 3TC, TDF is the currently preferred backbone for antiretroviral regimens worldwide.
One of the goals of treatment optimisation in low- and middle-income countries is to harmonise paediatric antiretroviral regimens with those for adults. Using TDF for children could offer this possibility -- although with current options, very young children and infants still need to be considered differently.
That these approvals, for children aged 2 to 12 (FDA approval for the 12-18 age group was in 2010 but EMA only gave this last year), took eleven years since adult approval in 2001 speaks volumes both of problems developing the formulations and lack of safety data in children.
Following the FDA approval, WHO published a review of the current literature and unpublished data on the safety and efficacy of TDF in this population.1
Overall, the review found that, based on the available data, TDF is efficacious in children and adolescents at current FDA-approved doses, but further studies are needed to confirm the dose and investigate the side-effects of TDF in combination with efavirenz in this population.
At CROI 2013, the lead author of the WHO review, Peter Havens, provided a brisk summary of what is known (and not known) about TDF use in children as part of a themed discussion.2 This session is worth watching and was followed by findings from two Thai paediatric cohorts; all were presented as posters.3-5 There was a great deal of discussion about what and how to monitor TDF in resource limited settings.
Jintanat Ananworanich showed pharmacokinetic (PK) data from 20 Thai adolescents aged 12-18 receiving TDF and boosted PI based second line regimens. Dr Ananworanich explained that they performed this investigation because TDF levels tend to be higher in Thai adults than those reported from high income countries, which can lead to higher rates of toxicity.
In this study, adherent adolescents had pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours samples taken after TDF dose. TDF was measured by HPLC. TDF dose was 210 mg/m2 once daily (maximum 300 mg). Geometric mean regression models evaluated predictors of higher TDF levels. The investigators also assessed renal toxicity.
Participants were a mean age of 15 years, weighed was 46 kg, had CD4 percent of 30%, and 75% were girls. Eighteen received lopinavir/ritonavir and the remaining 2 atazanavir/ritonavir. Nineteen participants took 300 mg TDF once daily and 1 took 300 mg on alternate days. The median duration of receiving TDF was 1.1 years.
Dr Ananworanich reported that concentrations matched those reported in published studies of adolescents from high-income counties receiving similar TDF doses. In multivariate analysis, lower GFR predicted higher AUC0-24, coefficient 0.995 (95% CI, 0.991 - 0.999), p = 0.02; and Clast 0.993 (95% CI 0.988-0.997), p=0.005. Higher ritonavir concentrations per body surface area also predicted higher Clast, 1.006 (95% CI 1.001-1.012), p=0.02.
No participants had abnormal serum creatinine, low glomerular filtration rate, glucosuria or tubular phosphate reabsorbtion levels. Four patients had evidence of proximal tubular injury: 3 proteinuria and 1 hyperuricosuria.
She concluded that although published studies have shown higher levels of several antiretrovirals in Thai patients, this one did not reveal elevated levels of TDF in adolescents and resulted in adequate PK and good short tem renal toxicity profile.
The second presentation by Virat Sirisathana was from a 48-week prospective study of TDF in children also receiving efavirenz.
Following enrollment, their ART was changed to a once-daily regimen of TDF/3TC/efavirenz. TDF was prescribed according to weight band dosing: 150 mg for 15 - <22 kg, 225 mg for 22 - <33 kg, and 300 mg for >33 kg.
The study also enrolled a control group of 40 children matched for age, gender, and CD4 receiving regimens without TDF. The investigators looked at renal function (glomerular, creatinine clearance [eGFR], tubular, calcium and phosphate excretion), as well as bone mineral density (BMD). BMD z-score (BMDZ) was calculated using age-matched healthy Thai children references: <2.5 was defined as low.
Dr Sirisathana that all participants except for 4(2 in each group) remained virologically suppressed. She reported a downward trend of estimated glomerular filtration rate (eGFR) for participants in both groups over 48 weeks. This change was significant in the group receiving TDF (179+48 vs 166+52 mL/min/1.73 m2), p = 0.02.
The fraction excretion of calcium and phosphate were slightly increased with time, but this was not significant. The investigators did not observe hypophosphatemia, proteinuria, or glucosuria.
Mean BMDZ decreased significantly in children receiving TDF from baseline to week 24 (0.01+SD 1.31 vs -0.43+1.12), p <0.01, but not between weeks 24 and 48. The change in mean BMDZ was significantly higher in the TDF than the control group at both time points.
Among participants with normal baseline, incidence of low BMDZ after starting TDF was 10.68 per 1000 patient-months in the study group vs 6.41 in the control group, p = 0.75.
Although there is still much that is unclear about the safety and efficacy of tenofovir in children, from an operational standpoint, harmonising treatment with that of adults, in children three years and above, is likely to hugely benefit scale up in resource limited settings and to be an option for this age group in the upcoming WHO guidelines.
The WHO Paediatric ARV Working Group has developed guidance on appropriate future TDF-containing paediatric fixed dose combinations (FDCs) and a simplified weight band-based dosing schedule.1
FDCs with 3TC are priority, these include:
The feasibility of scoring adult FDC tablets once on one side and twice on the other has been discussed but there is concern that in practice it may be difficult to manufacture, score and split large, multilayered FDC tablets in this way.
More data in children, particularly naive children, on TDF given with 3TC and EFV as well as appropriate formulations are urgently needed.
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