Published online November 15, 2005
PEDIATRICS Vol. 116 No. 6 December 2005, pp. e846-e854 (doi:10.1542/peds.2005-0975)

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ELECTRONIC ARTICLE

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Rohan Hazra, MD^*, Rachel I. Gafni, MD^*, Frank Maldarelli, MD, PhD^*,, Frank M. Balis, MD, Antonella N. Tullio, MD^*, Ellen DeCarlo, BSN^*, Carol J. Worrell, MD^*, Seth M. Steinberg, PhD^||, John Flaherty, PharmD^¶, Kitty Yale, BSc^¶, Brian P. Kearney, PharmD^¶ and Steven L. Zeichner, MD, PhD^*

^* HIV and AIDS Malignancy Branch
HIV Drug Resistance Program
Pediatric Oncology Branch
^|| Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland
^¶ Gilead Sciences, Foster City, California

Objectives. Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children.

Methods. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3–16.2 years) who had progressive disease with 2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks.

Results. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3–5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log₁₀ copies per mL (range: 4.1–5.9 log₁₀ copies per mL) to 4.21 log₁₀ copies per mL at week 48 (n = 15), with 6 subjects having <400 copies per mL, including 4 with <50 copies per mL. The overall median increases in CD4⁺ T cell counts were 58 cells per mm³ (range: –64 to 589 cells per mm³) at week 24 and 0 cells per mm³ (range: –274 to 768 cells per mm³) at week 48. The CD4⁺ cell responses among the virologic responders were high and sustained. The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log₁₀ copies per mL decreases in HIV plasma RNA levels.

Conclusions. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatment-experienced, HIV-infected children. Loss of BMD may limit tenofovir DF use among prepubertal patients.

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Key Words: tenofovir • HIV • children • multidrug resistance • bone toxicity

Abbreviations: HAART, highly active antiretroviral therapy • DF, disoproxil fumarate • BMD, bone mineral density • TAM, thymidine analog mutation • DTH, delayed-type hypersensitivity

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Accepted Jun 28, 2005.

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