In our first trial of TDF in HIV-infected children, using a 75 mg formulation of the drug, we saw BMD decreases of greater than 6% in 6 of the 15 subjects evaluated longitudinally (1
). Because of widespread TDF use and a report showing no effect of TDF on BMD in children (7
), we designed this study in a separate cohort of HIV-infected pediatric patients to provide more data on the use of TDF in HIV-infected children and adolescents. The study was terminated early due to administrative reasons, but we again showed BMD decreases of greater than 6% in one-third of subjects. BMD returned almost back to the baseline level in the one subject who required discontinuation of TDF because of the extent of her BMD loss.
Based upon this small study and our previous findings, TDF-containing HAART is associated with BMD loss, which tends to occur in heavily treatment-experienced pre-pubertal children or those in early puberty and seems to recover partially with discontinuation of TDF. Higher TDF exposures in smaller children, because a pediatric formulation is not available, may also contribute to the degree of BMD loss.
The one study (7
) showing no effect of TDF on BMD in children evaluated the effect of replacing stavudine and protease inhibitor-containing regimens with TDF/lamivudine/efavirenz on bone mineral accrual in 16 children aged 6 to 18 years. In contrast to our studies, these patients did not experience absolute bone loss after switching to TDF. The patients in the study by Giacomet et al (7
) were older, had greater height and weight z
scores than our patients, and the majority were in middle to late puberty or postpubertal. As our data suggest, TDF-related bone loss may be greater in less mature children. Their study design involved a potentially healthier population as subjects were required to have long-lasting viral suppression prior to the switch in therapy. Finally, because the patients in their study received TDF in the absence of ritonavir and were administered fractions of TDF pills to provide lower doses than the 300 mg tested by us, the tenofovir concentrations experienced by our patients may have been higher (2
The adverse effects of TDF on bone mineral acquisition during childhood must be better understood. The urgency of this issue is increased by the availability and appeal of TDF-containing fixed-dose combinations Atripla™ and Truvada® and the potential application of TDF as a means to prevent mother to child transmission of HIV. Furthermore, studies to investigate alternative TDF dosing regimens or appropriate adjuvant therapy in the pediatric HIV setting should be performed given the important role that TDF can play in an effective salvage regimen. Finally, careful monitoring of BMD (e.g., DXA at baseline and every 6–12 months) in HIV-infected children requiring treatment with TDF is indicated.