Why Tenofovir Disoproxil Fumarate is Avoided in Young HIV-Infected Children
Tenofovir disoproxil fumarate (TDF) is not recommended in HIV-infected children under 12 years of age or weighing less than 35 kg primarily due to significant concerns about bone mineral density loss and renal toxicity, which are more pronounced in younger children with higher rates of bone turnover during skeletal growth. 1, 2
Primary Safety Concerns
Bone Toxicity in Young Children
TDF causes significant decreases in bone mineral density (BMD) that are more severe in younger children compared to adolescents and adults, with the greatest effects observed in children under 10 years of age 2
In clinical studies, median z-scores for lumbar spine, femoral neck, and total hip BMD decreased significantly at 24 and 48 weeks of treatment, with absolute BMD decreases observed particularly in younger children (mean age 10.2 years vs 13.2 years in the stable group) 2
The mechanism involves stimulation of bone resorption, as evidenced by increases in bone turnover markers and calcium excretion, which is particularly problematic during periods of active skeletal growth 2
Children who experienced bone loss exceeding protocol allowances required TDF discontinuation, though partial or complete BMD recovery occurred after stopping the medication 2
Renal Toxicity Risk
Approximately 7.5% of children experienced serious adverse events requiring permanent TDF discontinuation, with half of these cases involving renal toxicity 3
The risk is substantially elevated when TDF is combined with other nephrotoxic medications, particularly ritonavir-boosted protease inhibitors and didanosine 3
A systematic review identified 250 renal adverse effects among 1,100 pediatric participants (21.6% affected), with 15 children requiring treatment discontinuation 4
FDA Labeling and Age Restrictions
Official Approval Status
The FDA approves TDF for children 12 years of age and older weighing ≥35 kg at the standard adult dose of 300 mg once daily 1
For children 2 to <12 years of age, TDF is approved only for HIV-1 infection (not hepatitis B) at weight-based dosing of 8 mg/kg daily (maximum 300 mg), but only for those weighing ≥17 kg who can reliably swallow intact tablets 1
Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established 1
Clinical Context and Risk-Benefit Considerations
Why the Age/Weight Cutoff Matters
Younger children have higher rates of bone turnover associated with normal skeletal growth, making them more vulnerable to TDF-related bone toxicity than adults 2
The correlation between bone loss and younger age suggests that young responders to antiretroviral therapy may be at greatest risk for bone toxicity 2
Dosing challenges exist with the available tablet formulation, leading to significant underdosing (37% received <80% of suggested dose) or overdosing (18% received >120%) in real-world pediatric use 3
Alternative Approaches for Younger Children
For children under 12 years requiring treatment, alternative NRTIs such as abacavir/lamivudine or zidovudine-based regimens should be prioritized 5
When TDF is absolutely necessary in younger children (e.g., for lamivudine-resistant hepatitis B with severe hepatitis), it represents the only available choice but requires intensive monitoring 6
Regular monitoring of renal function is warranted in high-risk patients, particularly those on concurrent nephrotoxic drugs 5, 4
Important Clinical Caveats
The benefits of TDF (once-daily dosing, efficacy against hepatitis B, no multi-NRTI resistance mutations) must be carefully balanced against toxicity risks in the pediatric population 5
Long-term data on renal and bone outcomes in HIV-infected children remain limited, necessitating cautious use and close monitoring when TDF is prescribed 5, 4
Tenofovir alafenamide (TAF) formulations may offer improved bone and renal safety profiles compared to TDF, though specific pediatric data for very young children remain limited 6