Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy: Impact on Bone Mineral Density in HIV-Infected Children

Abstract

Tenofovir disoproxil fumarate use in children seems to be associated with decreases in bone mineral density that, in some children, stabilize after 24 weeks. Increases in bone markers and calcium excretion suggest that tenofovir disoproxil fumarate may stimulate bone resorption. Bone turnover is higher in children than in older adolescents and adults because of skeletal growth, potentially explaining the greater effect seen in young children. Decreases in bone mineral density correlate with decreases in viral load and young age, suggesting that young responders may be at greater risk for bone toxicity.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

“…Studies of TDF ‐associated bone toxicity in treatment‐experienced children yielded conflicting results 119. A significant loss of bone mineral density (BMD) was observed in young and pre‐pubertal children, and in those who received higher exposures to TDF because of higher doses or concomitant use of PIs 120, 121. Reassuringly, in most children on TDF‐containing ART, BMD z ‐scores after an initial decrease tend to stabilize 121, 122, 123.…”

“…A significant loss of bone mineral density (BMD) was observed in young and pre‐pubertal children, and in those who received higher exposures to TDF because of higher doses or concomitant use of PIs 120, 121. Reassuringly, in most children on TDF‐containing ART, BMD z ‐scores after an initial decrease tend to stabilize 121, 122, 123. Although the clinical significance of delayed bone mineralization has not been established, the concern is that suboptimal bone accrual in childhood and failure to achieve expected peak bone mass could result in increased fractures in adulthood.…”

Renal and Bone Adverse Effects of a Tenofovir-Based Regimen in the Treatment of HIV-Infected Children: A Systematic Review

“…Nineteen studies (two RCTs [23,24], nine non-randomised and observational studies [9,10,14,15,[25][26][27][28][29], four case reports [12,[30][31][32] and four case series [13,[33][34][35]) that reported the presence of renal and bone adverse effects of TDF-containing regimen were identified, including a total of 1100 study participants. The various study designs for the non-randomised and observational studies included, three single arm open label trials [9,14,15], two retrospective cohorts studies [10,25], one cross-sectional evaluation study [26] and three prospective cohort studies [27][28][29], of which one involved retrospective and prospective data collections in a two-phase design.…”

“…The majority of TDF toxicities have been investigated in individuals over 18 years of age, but there are some recent data from studies in children and adolescents. Two studies in children receiving TDF as part of their HAART regimens showed a favourable safety profile for the drug [9,11], whereas renal toxicity mainly affecting the renal tubules has been described in some paediatric cohort studies [10,[12][13][14]. A further safety concern for TDF use in children is the potential for adverse effects on bone metabolism.…”

“…Tenofovir-containing HAART is associated with >6% loss in bone mineral density (BMD) in one-third of children. This tends to occur in heavily treatmentexperienced prepubertal children or those in early puberty, and seems to recover partially with discontinuation of TDF [14,15]. This systematic review is aimed at identifying and summarising the reports of renal and bone adverse effects of tenofovir based regimen in HIV-infected children from 2 to 19 years of age.…”