Tenofovir studies in children

Brian Kearny and colleagues from Gilead and the Albert Einstein School of Medicine in New York evaluated the PK of a single dose of an investigational oral suspension of tenofovir (TDF, Viread). [1]

Seven boys and five girls aged between two and eight years received a single 8mg/kg dose, selected based on results of previous studies in older children. All children were already on HAART regimens with either undetectable or low level viraemia (range 1.69-4.31 log10 copies/mL).

As a group, the children produced a similar mean concentration-time profile to the adult 300mg dose. Although there were only small numbers in this study (n=3 aged 2-4; n=5 aged 5-6 and n=4 aged 6-8) lower mean concentrations correlated with lower age, and as with adults there was a range of interpatient variability (AUC24hr range approx 1125-4125 ng.hr/mL in children vs 1875-4500 ng.hr/mL in adults).

Cmax and Tmax were similar to mean adult values and no treatment related side effects or laboratory abnormalities were reported.

In a second study, Hazra and colleagues from Bethesda MD reported 48-week results from using tenofovir plus optimised background regimen in 19 treatment experienced children median age 11.9 years (range 6.2 to 16.2) in a Phase I paediatric study. Safety monitoring included routine laboratory studies and additional monitoring for bone toxicity by dual-energy x-ray absorptiometry (DEXA) of the lumbar spine. [2]

Median time of prior ARV therapy was 9.7 years (range 4.8 to 13.5). Baseline resistance testing showed median of 9 (range six to 14) major RT mutations and eight (two to 10) major protease mutations. Baseline CD4 and viral load count was 206 cells/mm3 (0 to 766) and 5.4 log10 copies/mL (4.1 to 5.9) respectively.

At week 48 (n=14) median increase in CD4 count was 4 cells/mm3 (-274 to 768) and decrease in viral load was -1.52 logs (-4.0 to 0.52). HIV RNA was <50 copies/mL in four children (<400 copies/mL in six children).

Four subjects discontinued TDF for elevated transaminases (one before TDF dosing, two during the TDF monotherapy phase, and one at week 18). One child died at week 34 from an intracranial haemorrhage unrelated to TDF; one child was removed from study at week 43 for disease progression. At week 24, the median (range) decrease BMD Z-score was -0.38 (-1.2 to 0.52); 10 subjects had decreases in BMD from baseline, seven of whom were virologic responders (viral load decreases from -1.57 to -4.0). At week 48, the median (range) decrease in BMD Z-score from baseline was -0.31 (-2.9 to 0.21); five subjects had decreases in BMD from baseline, and all five had virologic responses (from -2.15 to -4.0).

Comment

The authors concluded that TDF-containing combination antiretroviral therapy is virologically active for at least 48 weeks in heavily treatment-experienced children, but can be associated with decreased bone mineral density. Further efficacy, toxicity, and tolerability studies are ongoing. The relationship between lower BMD and virologic response should also be studied. Substantially reduced BMD in children has already been reported (Vignano et al) and been linked to HAART therapy and should be taken very seriously.