Background:  Tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor is approved for use in adults, but not children. Metabolic bone changes have been seen in young animals given high-dose TDF and in HIV-infected adults treated with TDF. Despite concern that children may be at greater risk of bone toxicity than adults, TDF is used off-label in pediatrics. We present data on bone toxicity through 96 weeks from a phase 1 study of TDF-containing HAART in heavily treatment-experienced HIV-infected children.

Methods:  As part of HAART for as long as 96 weeks, 15 heavily treatment-experienced HIV-infected children (mean age ± SD, 12±2 years), failing salvage therapy, received TDF 175 to 350 mg/m²/day (adult dose equivalent). Bone mineral density of the lumbar spine, femoral neck, and hip by dual-energy X-ray absorptiometry, metabolic bone markers, and 24-hour urine calcium excretion were measured at 0, 24, 48, 72, and 96 weeks. Comparisons between time points were made using a paired t-test for normally distributed data and a Wilcoxon signed rank test for data not normally distributed.

Results:  Baseline mean (± SEM) Z-scores (SD scores compared to matched controls) were below zero (lumbar spine–1.02±0.3, hip –0.8±0.4, femoral neck –1.0±0.5).Mean lumbar spine, femoral neck, and hip Z-scores decreased further by 24 and 48 weeks and stabilized thereafter in most patients. Absolute decreases in bone mineral density were observed in 6 children, who tended to be younger. The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment (r² = 0.275, p <0.05).Metabolic markers of bone formation and resorption were variable but tended to increase. At 24 weeks, 24-hour urine calcium excretion was increased compared with baseline (4.2±1.0 vs 2.9±0.9 mg/kg/d, p <0.05). However, 2 children, in whom TDF was discontinued at 48 weeks because of significant bone loss, demonstrated recovery of lumbar spine bone mineral density by 96 weeks.

Conclusions:  TDF was an effective component of HAART in HIV-infected children requiring salvage therapy, but was associated with decreases in bone mineral density. Increases in bone markers and calcium excretion suggest that TDF may stimulate bone resorption. Bone turnover is higher in children because of skeletal growth, possibly explaining the greater effect seen in children than in adults. While the long-term effects on bone are unknown, careful monitoring of HIV-infected children receiving treatment with TDF is warranted.