title: Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403.
abstract: BACKGROUND
  Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children. We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an NRTI, protease inhibitors +/- a nonnucleoside reverse transcription inhibitor (NNRTI).
  
  
  METHODS
  This was a phase II, randomized, multicenter study. Forty-one children and youths between 5 months and 21 years with prior NRTI and no prior NNRTI or protease inhibitor experience received either nelfinavir (NFV) 30 mg/kg twice daily (bid), ritonavir (RTV) 400 mg/m bid and buffered didanosine (ddI) 240 mg/m daily (arm A) or NFV 50-55 mg/kg bid, nevirapine (NVP) 120 mg/m bid and stavudine (d4T) 1 mg/kg bid (arm B). Patients were evaluated clinically for 48 weeks after initiation of therapy. Intensive pharmacokinetic sampling occurred after 4 weeks of therapy.
  
  
  RESULTS
  : The proportion of children with HIV-1 RNA < or =400 copies/mL and on randomized treatment at 48 weeks was 65% among children assigned NFV + RTV + ddI versus 28% among those assigned NFV + NVP + d4T (P = 0.039). No significant difference in median CD4% change from baseline to week 48 was found (3% versus 1%). No significant differences in safety or tolerability between children randomized to NFV + RTV + ddI versus NFV + NVP + d4T were identified. However, a trend toward a higher rate of permanent discontinuation of study treatment was noted among children assigned to NFV + NVP + d4T compared with NFV + RTV + ddI [7 of 20 (35%) versus 2 of 21 (10%); P = 0.12]. NFV pharmacokinetic measurements were not statistically different between the treatment groups, yet exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV. The pharmacokinetics for NVP, RTV and d4T were similar to those of previously reported data.
  
  
  CONCLUSIONS
  : Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containing NFV + NVP + d4T. Differences in tolerability between the 2 treatment groups were not identified. Systemic exposure of these drugs was similar to that reported in other HIV-infected children and adults.
authors.affiliation: University of Alabama at Birmingham, Birmingham, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: King
authors.forename: Sharon
authors.initials: S
authors.lastname: Nachman
authors.forename: Ram
authors.initials: R
authors.lastname: Yogev
authors.forename: Janice
authors.initials: J
authors.lastname: Hodge
authors.forename: Grace
authors.initials: G
authors.lastname: Aldrovandi
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hughes
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Wiznia
authors.forename: Bharat
authors.initials: B
authors.lastname: Damle
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D002675:Child, Preschool; D016049:Didanosine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D019888:Nelfinavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019829:Nevirapine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018119:Stavudine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D018119:Stavudine; D019888:Nelfinavir; D016049:Didanosine; D019438:Ritonavir