title: Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection.
abstract: OBJECTIVE
  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 > or = 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.
authors.affiliation: HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rohan
authors.initials: R
authors.lastname: Hazra
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Antonella N
authors.initials: AN
authors.lastname: Tullio
authors.forename: Ellen
authors.initials: E
authors.lastname: DeCarlo
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Worrell
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: John
authors.initials: J
authors.lastname: Flaherty
authors.forename: Kitty
authors.initials: K
authors.lastname: Yale
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
authors.forename: Steven L
authors.initials: SL
authors.lastname: Zeichner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000627:therapeutic use*; D016879:Salvage Therapy; D000068698:Tenofovir; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine