Antiretroviral drugs, mainly protease inhibitors (PIs), have been suggested to be contributory factors to decreased bone mass in HIV-infected adults. Reduced bone mass has been found in HIV-infected children as well, although the role of infection per se or of antiretroviral treatment as a causative factor is still unclear.1 Recently, concerns have been raised about tenofovir (TDF)-induced bone mineral loss. A remarkable but nonprogressive decrease in lumbar spine bone mineral density (BMD) was observed, between 24 to 48 weeks, in antiretroviral-naive adults treated with TDF compared with patients treated with stavudine (d4T) in a randomized double-blind study over 144 weeks.2 The follow-up study showed that the incidence of osteoporosis and osteopenia was similar between the 2 treatment arms, however.3 The safety of TDF has also been evaluated in a pediatric population. In a recent study, 19 heavily antiretroviral-experienced children and adolescents (mean age = 11.9 years, range: 6.2-16.2 years) were treated with highly active antiretroviral therapy (HAART) containing TDF; safety and clinical responses were evaluated at 48 weeks, and the effect on bone was monitored by measuring lumbar spine BMD by dual-energy x-ray absorptiometry (DXA). TDF has been efficient in maintaining a low viral load and in having a good clinical response. Short-term TDF treatment was associated with a median decrease of 0.31 (range: −2.9 to 0.21) in the BMD z-score from baseline.4 Another study assessed BMD measured by DXA in 7 vertically HIV-infected children (mean age = 14 years, range: 6-19 years). The assessment was performed before and after TDF use in 3 and 4 cases respectively; 6 patients showed a low lumbar spine BMD z-score. BMD measurements were repeated in 4 patients after approximately 1 year, showing no progression of bone mass loss.5
The aim of our study was to assess whether the substitution of d4T with TDF would result in decreased bone mineral content (BMC) and BMD accrual in HIV-infected children.
SUBJECTS AND METHODS
We evaluated 16 white HIV-infected children (mean age = 13.3 years, range: 6.4-17.9 years) on stable HAART (mean exposure = 69 months) containing lamivudine plus d4T plus 1 PI (indinavir in 6 cases, ritonavir in 6 cases, and nelfinavir in 4 cases) and with long-lasting viral suppression (HIV-RNA load <50 copies/mL for at least 48 weeks) who were switched to a lamivudine (3TC)/TDF/efavirenz regimen. This group of patients is part of a larger group of children who are being monitored for a switch therapy study. TDF was administered once daily at body surface area-dependent doses: 150 mg for 0.5 to 0.84 m2, 225 mg for 0.84 to 1.29 m2, and 300 mg for ≥1.3 m2. All patients were clinically stable and with weight (46.7 [16.2] kg) and height (153.4 [18.1] cm) within reference ranges. The mean height and weight z-scores at baseline were −0.21 (1.0) and −0.35 (1.0), respectively. All the patients had normal sexual development: at baseline, 5 were prepubertal, 3 were in midpuberty (Tanner stage 2 or 3), and the remaining were in late puberty (Tanner stage 4 or 5).
As control group, we included in the study 166 healthy volunteers (HCs) of white origin with a mean of age 13.1 years, ranging from 5.7 to 19.9 years. Their pubertal development stage ranged from Tanner stage 1 to 5. All subjects were in good health, and none of them had a history of endocrine, nutritional, growth, or renal problems. Informed consent was obtained from the parents or legal guardians of each patient and HC before participation. The study was approved by the Ethical Committee of the L. Sacco Hospital.
BMC and BMD were measured at the L2 to L4 vertebrae level and in the whole skeleton by DXA (DPX-L; Lunar Radiation Corporation, Madison, WI). The reproducibility of our instrument is 0.6% with the standard phantom, 1.4% for the lumbar spine, and 1.5% for the whole skeleton in vivo. Bone mineral measurements were obtained 12 months before the switch (T−12), at the switch (T0), and 12 months after the switch (T+12). Expected changes in bone mineral measurements were calculated from cross-sectional data of HCs by regression analyses, as described elsewhere.6 Briefly, bone mass measurements were plotted against age, and anticipated changes were calculated using regression curves.
Comparisons between observed and expected BMC and BMD changes were made using t tests for paired samples. All statistical analyses were conducted at the α = 0.05 level and were 2-tailed.
All patients remained clinically stable and retained virologic control with an HIV-RNA level <50 copies/mL through the study period. At T−12, T0, and T+12, the mean lumbar spine BMC and BMD values were 24.1, 31.4, and 35.0 g and 0.81, 0.905, and 0.97 g/cm2, respectively. At the same intervals, the mean total body BMC and BMD values were 1380, 1766, and 1917 g and 0.89, 1.008, 1.04 g/cm2, respectively. Bone mass measurement changes during the study period are shown in Table 1. The BMC and BMD increments observed before switching therapy did not differ from those expected in the lumbar spine as well as in the whole skeleton. Similarly, the changes detected during treatment with TDF did not differ significantly from the ones calculated in HCs.
The current study shows that switching antiretroviral treatment to TDF does not impair bone mineral accrual in HIV-infected children. Our results are apparently different from those of previous pediatric studies4,5; several factors may account for the discrepancies. Our patients were in good health, and their antiretroviral treatment before switching was successful; conversely, previous studies were conducted in heavily experienced patients in treatment failure.4,5 Bone mass measurements obtained with DXA are largely influenced by the size of the bone. It is important to note that the z-score does not correct for differences in bone size; therefore, it should be avoided when comparing growing individuals. Previous studies have monitored bone mass changes through changes of z-scores,4,5 whereas we compared the BMC and BMD increases of HIV patients with those calculated from a large sample of HCs. Both procedures represent a surrogate for the lack of longitudinal data in healthy children and may not represent accurately the physiologic changes occurring during growth. We could not obtain longitudinal data from healthy controls, because it was not considered ethical by the institutional review boards at our institutions, despite the low amount of radiation exposure involved in such studies. We thus calculated the expected BMC and BMD changes based on cross-sectional data. The large number of healthy children was needed to increase the accuracy of such a procedure. Another important issue in bone mass accrual is represented by pubertal development: bone density increases as a function of pubertal stage,7,8 and delays in pubertal development lead to decreased bone mass.8 We calculated the BMC and BMC changes based on age. Nevertheless, comparing age-based changes in this study was deemed appropriate, because all our patients showed proper sexual development.
Our data suggest that 12 months of treatment with TDF at the indicated doses is not detrimental for bone mineral accrual in HIV-infected children. The TDF dosage was chosen based on previous studies.4,5 Our patients were already on a stable and successful HAART regimen, and their changes in BMC and BMD at both sites measured were as expected for healthy children. Switching antiretroviral treatment did not change the situation, and our patients increased their bone mass as expected. We recognize that the small sample size may be a limitation of this study and that there is a need to confirm the bone safety of TDF in a larger number of HIV-infected children.
1. Viganò A, Mora S. Adverse effects of antiretroviral therapy: focus on bone density. Expert Opin Drug Saf
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DF vs stavudine in combination therapy in antiretroviral-naive patients. A 3-year randomized trial. JAMA
3. Powderly W, Cohen C, Gallant J, et al. Similar incidence of osteopenia and osteoporosis in ART-naïve patients treated with tenofovir
DF or stavudine in combination with lamivudine or efavirenz over 144 weeks [abstract 823]. Presented at: 12th Conference on Retrovirus and Opportunistic Infections; 2005; Boston.
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DF in combination with other antiretrovirals in heavily treatment-experienced HIV-infected children
: data through 48 weeks [abstract 928]. Presented at: 11th Conference on Retrovirus and Opportunistic Infections; 2004; San Francisco.
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disoproxil fumarate (TDF) in heavily pretreated HIV-infected children
[abstract TuPeB4465]. Presented at: 15th International AIDS Conference; 2004; Bangkok.
6. Mora S, Zamproni I, Beccio S, et al. Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated HIV-infected children
. J Clin Endocrinol Metab
7. Gilsanz V, Roe TF, Mora S, et al. Changes in vertebral bone density in black girls and white girls during childhood and puberty. N Engl J Med
8. Mora S, Gilsanz V. Establishment of peak bone mass. Endocrinol Metab Clin North Am