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Background:  Tenofovir DF (TDF) is a nucleotide analog HIV reverse transcriptase (RT) inhibitor approved for treatment of adults. We report safety and clinical responses through 48 weeks from a pediatric phase I study of TDF combined with other antiretrovirals (ARV).

Methods:  The 19 subjects’ median age (range) was 11.9 years (6.2 to 16.2). TDF was given alone for 6 days followed by addition of optimized ARV background regimens. Patients were monitored by HIV RNA RT-PCR, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density by dual-energy x-ray absorptiometry (DEXA).

Results:  Subjects had extensive treatment experience: median (range) time of prior ARV therapy was 9.7 years (4.8 to 13.5). Baseline resistance testing showed median (range) of 9 (6 to 14) major RT mutations and 8 (2 to 10) major protease mutations. At baseline, median (range) CD4⁺ T-cell count was 206 cells/mL (0 to 766); median (range) log₁₀ HIV RNA was 5.4 (4.1 to 5.9). At week 24 (n = 16) median (range) increase in CD4⁺ T-cell count was 58 cells/mL (-64 to 589); median (range) decrease in log₁₀ HIV RNA was -0.53 (-4.0 to 0.31). HIV RNA was <50 copies/mL in 4 children (<400 copies/mL in 6 children). At week 48 (n = 14) median (range) increase in CD4⁺ T-cell count was 4 cells/mL (-274 to 768); median (range) decrease in log10 HIV RNA was -1.52 (-4.0 to 0.52). HIV RNA was <50 copies/mL in 4 children (<400 copies/mL in 6 children). Four subjects discontinued TDF for elevated transaminases (1 before TDF dosing, 2 during the TDF monotherapy phase, and 1 at week 18). One child died at week 34 from an intracranial hemorrhage 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, 7 of whom were virologic responders (decreased log₁₀ HIV RNA 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); 5 subjects had decreases in BMD from baseline, and all 5 had virologic responses (decreased log₁₀ HIV RNA from -2.15 to -4.0). Regimens were otherwise well-tolerated.

Conclusions:  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.

Keywords: pediatric HIV/AIDS; tenofovir DF; drug resistance