A Study of the Safety and Effectiveness of Treating Advanced AIDS Patients Between Ages 4 and 22 With 7 Drugs, Some at Higher Than Usual Doses
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to see if 7 drugs, some of them given at higher doses than
      normal, are safe and tolerated by young patients with AIDS who have failed to respond to
      other treatments. The study will also see what effect taking several anti-HIV drugs together
      at high doses has on the body's ability to fight HIV infection. The 7 drugs that will be
      given in this study are stavudine (d4T), didanosine (ddI), lamivudine (3TC), nelfinavir
      (NFV), ritonavir (RTV), saquinavir (SQV), and nevirapine (NVP).

      (This study has been changed from an 8-drug regimen to a 7-drug regimen. Patients no longer
      receive the drug hydroxyurea [HU].) Doctors are seeing many HIV-positive children who did not
      get good long-term results from the current anti-HIV drugs. Some doctors believe anti-HIV
      drugs fail because drug levels in the body are too low. In this study, doctors will give
      patients 7 drugs, some at higher doses than normal. Since it is very important that patients
      on the study take all of these drugs, doctors will make it as easy as possible. Doctors want
      to try this because children with advanced AIDS have few treatment choices.
    

Detailed description: 
      Clinicians are increasingly confronted with HIV-positive children who have failed all
      available antiretroviral therapies and have few viable treatment options. Virologic failure
      in these patients may be a result of antiretroviral resistance, likely a result of poor
      adherence to the treatment regimen or inadequate dosing. This study is designed to achieve
      adherence through observation of drug administration for the first 8 weeks of the study and
      to further overcome resistance by intensive, high-dose, multi-drug therapy. Treatment with
      more than 4 drugs has not been studied formally in children, but pediatricians caring for
      children with AIDS have used such strategies off study with success. Dose intensification may
      also aid in overcoming resistance; therefore, in this trial, d4T, 3TC, and NFV are
      administered at up to twice their standard doses. Given the limited therapeutic options
      available to HIV-positive children with poor prognoses, high-dose, multi-drug therapy merits
      study. [AS PER AMENDMENT 01/07/00: Pancreatitis, which may be fatal in some cases, has
      occurred during therapy with ddI. The risk of pancreatitis may be increased when ddI is used
      in combination with HU. ACTG A5025, a study that had a d4T/ddI/HU arm, was terminated because
      of significant toxicity concerns related to the HU-containing arm. Patients enrolled in ACTG
      P1007 may be at increased risk of developing pancreatitis given their advanced disease state
      and the use of multiple drugs including HU. The study had been amended to address these
      concerns.] [AS PER AMENDMENT 12/19/01: HU has been removed from the drug regimen.]

      Patient enrollment is staged to allow study physicians to aggressively monitor patients for
      signs of toxicity. Initially, patients are admitted to a hospital or clinical research center
      for 2 weeks, where they initiate an [AS PER AMENDMENT 12/19/01: "8-drug regimen" is replaced
      by "7-drug regimen"] and undergo frequent physical exams and blood tests to assess [AS PER
      AMENDMENT 12/19/01: glucose levels], pharmacokinetics, virologic response, and toxicity. If
      investigators identify important drug interactions requiring modification of the combination
      regimen, or if there are early regimen-terminating toxicities, the trial will be halted to
      address these concerns. After 2 weeks, the patient is discharged to return home. Study
      personnel visit the patient's house twice a day for 6 more weeks to observe drug
      administration, and the patient continues to receive regular physical exams and blood tests.
      At the end of Week 24, all patients with plasma RNA levels of 10,000 copies/ml or less are
      offered the opportunity to continue their regimen to Week 48. Patients with plasma RNA levels
      above 10,000 copies/ml at Week 24 and patients who experience virologic rebound at or after
      Week 24 are taken off study unless the patient's family and the investigator feel it is in
      the best interest of the child to remain on study. [AS PER AMENDMENT 12/19/01: The 2-week
      hospital or GCRC stay is no longer required. A 2-day stay in a hospital or GCRC for the
      purpose of drug regimen training is recommended, but not mandatory. Study personnel visit the
      patient once a day for 6 weeks at an agreed upon location or by phone contact.
    

Intervention name(s): Ritonavir; Nelfinavir mesylate; Saquinavir; Nevirapine; Lamivudine; Stavudine; Didanosine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Ritonavir; Nelfinavir; Saquinavir; Lamivudine; Nevirapine; Stavudine; Didanosine
Primary purpose: Treatment
Keywords: Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Protease Inhibitors; Reverse Transcriptase Inhibitors; Salvage Therapy; Anti-HIV Agents