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

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.

Inclusion criteria

Patients may be eligible for this trial if they:

• Are HIV-positive.
• Have HIV levels of 10,000 copies/ml or more.
• Are between ages 4 and 22.
• Have motivation and ability to conform to the complex treatment regimen.
• Agree to practice abstinence or use 2 effective methods of birth control during the study and until 3 months after stopping the study drugs, if sexually active.
• Have written informed consent from a parent or legal guardian if under age 18.
• Have used at least 3 different nucleoside reverse transcriptase inhibitors (NRTIs) for at least 3 months each or have shown resistance to at least 3 different NRTIs.
• Have used at least 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) for at least 3 months each or have shown resistance.
• Have used at least 2 different courses of a protease inhibitor (PI)-containing regimen, each of which was at least 6 months, or have evidence of mutations to at least 2 different PIs.
• This study has been changed. The inclusion criteria reflects a change in the prior anti-HIV therapy required, age requirement, and the required CD4 and HIV levels.

Exclusion criteria

Patients will not be eligible for this trial if they:

• Are allergic to even 1 study drug or have ever had to stop 1 of these drugs because of a bad reaction to it.
• Have a history of diabetes, hepatitis C, hepatitis B, or certain diseases of the nervous system, heart, or pancreas.
• Have had a serious infection within 14 days of starting the study.
• Need certain drugs that interact with the study drugs. (See Technical Summary for more details.)
• Are pregnant or breast-feeding.
• Have had hepatitis within 30 days of study entry.