Published online August 21, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e711-e718 (doi:10.1542/peds.2005-2525)

This Article Full Text Full Text (PDF) Submit a response View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gafni, R. I. Articles by Zeichner, S. L. Search for Related Content PubMed PubMed Citation Articles by Gafni, R. I. Articles by Zeichner, S. L. Related Collections Infectious Disease & Immunity Social Bookmarking                         What's this?

ARTICLE

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

Rachel I. Gafni, MD^a,b, Rohan Hazra, MD^a, James C. Reynolds, MD^c, Frank Maldarelli, MD, PhD^d, Antonella N. Tullio, MD^a, Ellen DeCarlo, BSN^a, Carol J. Worrell, MD^a, John F. Flaherty, PharmD^e, Kitty Yale, BSc^e, Brian P. Kearney, PharmD^e and Steven L. Zeichner, MD, PhD^a,f

^a HIV and AIDS Malignancy Branch, National Cancer Institute
^c Nuclear Medicine Department, Clinical Center
^d National Cancer Institute HIV Drug Resistance Program, National Institutes of Health, Bethesda, Maryland
^e Gilead Sciences, Inc, Foster City, California;
^b Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland;
^f Departments of Pediatrics and Microbiology, Immunology, and Tropical Medicine, George Washington University School of Medicine, Division of Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC

OBJECTIVE. Tenofovir disoproxil fumarate, a nucleotide analog HIV reverse transcriptase inhibitor with demonstrated activity against nucleoside-resistant HIV, is approved for use in adults but not children. Metabolic bone abnormalities have been seen in young animals given high-dose tenofovir and HIV-infected adults that were treated with oral tenofovir disoproxil fumarate. However, tenofovir disoproxil fumarate is being used in children despite a lack of bone safety data. We hypothesized that, given the higher rate of bone turnover that is associated with normal skeletal growth, the potential for TDF-related bone toxicity may be greater in children than in adults.

METHODS. Fifteen highly antiretroviral-experienced HIV-infected children who were 8 to 16 years of age (mean ± SD: 12 ± 2) and required a change in therapy received tenofovir disoproxil fumarate 175 to 300 mg/m² per day (adult dose equivalent) as part of highly active antiretroviral therapy for up to 96 weeks. Bone mineral density of the lumbar spine, femoral neck, and total hip by dual-energy x-ray absorptiometry and blood and urine markers of bone metabolism were measured at 0, 24, 48, 72, and 96 weeks.

RESULTS. Median z score (SD score compared with age, gender, and ethnicity-matched control subjects) of the lumbar spine, femoral neck, and total hip were decreased from baseline at 24 weeks and 48 weeks and then stabilized. Lumbar spine bone mineral apparent density (which estimates volumetric bone mineral density independent of bone size) z scores also decreased at 24 weeks. Absolute decreases in bone mineral density were observed in 6 children; the mean age of these children was significantly younger than the bone mineral density stable group (10.2 ± 1.1 vs 13.2 ± 1.8 years). The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment. Metabolic markers of bone formation and resorption were variable. Two children in whom tenofovir disoproxil fumarate was discontinued because of bone loss that exceeded protocol allowances demonstrated partial or complete recovery of bone mineral density by 96 weeks.

CONCLUSIONS. 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.

---

Key Words: bone mineral density • HIV • bone mineralization • antiretroviral therapies

Abbreviations: BMD—bone mineral density • HAART—highly active antiretroviral therapy • TDF—tenofovir disoproxil fumarate • LS—lumbar spine • PTH—parathyroid hormone • FN—femoral neck • TH—total hip • DXA—dual-energy x-ray absorptiometry • BMAD—bone mineral apparent density

---

Accepted Mar 20, 2006.

CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D. Nurutdinova, N. F Onen, E. Hayes, K. Mondy, and E T. Overton Adverse Effects of Tenofovir Use in HIV-Infected Pregnant Women and their Infants Ann. Pharmacother., November 1, 2008; 42(11): 1581 - 1585. [Abstract] [Full Text] [PDF]

				K. K. A. Van Rompay, L. Durand-Gasselin, L. L. Brignolo, A. S. Ray, K. Abel, T. Cihlar, A. Spinner, C. Jerome, J. Moore, B. P. Kearney, et al. Chronic Administration of Tenofovir to Rhesus Macaques from Infancy through Adulthood and Pregnancy: Summary of Pharmacokinetics and Biological and Virological Effects Antimicrob. Agents Chemother., September 1, 2008; 52(9): 3144 - 3160. [Abstract] [Full Text] [PDF]

eLetters:

Read all eLetters

Tenofovir and bone mineral density

Anne Sutcliffe

Pediatrics Online, 22 Jan 2007 [Full text]