Salvage Treatment, Resistance Testing, and Withdrawal of Anti-HIV Drugs for HIV Patients Failing Current Anti-HIV Treatment

Phase III Evaluation of the Role of Temporary Cessation of Antiretroviral Treatment and Resistance Testing-Based Selection of Antiretroviral Drugs in the Virologic Response to Salvage Therapy for Heavily Treatment-Experienced HIV-Infected Individuals Failing Current Antiretroviral Therapy

The purpose of this study is to test another way to control the amount of HIV in the blood (viral load).

Studies show that stopping all anti-HIV drugs for a time before switching to new anti-HIV drugs may improve the response in some individuals who are failing treatment. Other studies suggest a benefit if drug-resistance tests are used in selecting a new anti-HIV drug treatment. This study tests the effect of stopping anti-HIV drugs for a time before switching to anti-HIV drugs selected using drug-resistance test results.

Virologic failure occurs in a large proportion of individuals receiving treatment with combination antiretroviral therapy. Studies suggest that treatment interruption prior to initiation of a multiple-drug rescue regimen may improve virologic response in individuals who have failed several prior antiretroviral regimens. Other studies suggest there is a virologic benefit derived from using genotypic or phenotypic resistance testing in selecting salvage therapy regimens for patients failing antiretroviral therapy. This study tests the hypothesis that salvage regimens selected on the basis of HIV-1 resistance genotype, phenotype [AS PER AMENDMENT 02/19/02: virtual phenotype], and treatment history will be more effective if there is a period of treatment interruption before initiating that regimen.

Patients continue their antiretroviral therapy until randomization. Based on the results of the pre-entry genotype and phenotype [AS PER AMENDMENT 02/19/02: virtual phenotype] tests and treatment history, an individualized salvage therapy regimen (not provided by the study) is selected by the site investigator(s). Additionally, patients start or continue maintenance therapy (not provided by the study) for opportunistic infections (OIs). Patients are randomized to 1 of 2 treatment arms. In Arm A, patients have antiretroviral treatment interruption for a period of 16 weeks (Step 1), followed by initiation of the [AS PER AMENDMENT 02/19/02: best available] salvage therapy regimen (Step 2). [AS PER AMENDMENT 02/19/02: Patients in Arm A will be placed immediately on their individualized salvage regimen before the end of the 16-week period of treatment interruption if their CD4 count falls below a defined threshold, or if they develop a new OI]. In Arm B, patients switch immediately to the salvage therapy regimen. [AS PER AMENDMENT 02/15/01: Patients who become pregnant during Step 1 of Arm A must be advised to begin their selected, individualized salvage therapy regimen or a modified salvage regimen. Patients who become pregnant during Step 2 of Arm A or Arm B have therapy evaluated and undergo any changes required by their pregnancy.] Patients in both arms are monitored for plasma HIV-1 RNA levels, CD4+ and CD8+ cell counts, and HIV drug resistance genotypes and phenotypes for a duration of 64 weeks from randomization. Patients in Arm A are also monitored for immune reactivation by measurement of T-cell subsets and plasma cytokines during treatment interruption. Patients may participate in a virology substudy (A5100s) and an immunology substudy (A5104s). [AS PER AMENDMENT 02/19/02: Patients who volunteer to participate in the substudies must be registered to the main study at the same time they are registered to a substudy.]

Inclusion Criteria

Patients may be eligible for this study if they:

• Are HIV-infected.
• Are likely to have drug-resistant HIV from having taken all types of anti-HIV drugs (protease inhibitors [PIs], nucleoside reverse transcriptase inhibitors [NRTIs], and nonnucleoside reverse transcriptase inhibitors [NNRTIs]), and having failed treatment prior to the current treatment for reasons other than toxicity.
• Are currently receiving anti-HIV treatment with at least 3 drugs. Low doses of ritonavir (100 to 200 mg twice daily) taken with 1 other PI is counted as a single PI.
• Are currently failing treatment due to a high viral load (amount of HIV in the blood).
• Have had a new anti-HIV drug combination selected.
• Are at least 18 years old.
• This study has been changed to remove CD4 counts as an inclusion criterion. In the previous version of the protocol, patients were required to have a CD4 count of 150 cells/ml or more within 42 days prior to study entry.

Exclusion Criteria

Patients will not be eligible for this study if they:

• Have stopped treatment for more than 4 weeks in the past 6 months.
• Are pregnant or breast-feeding.
• Have cancer that requires systemic treatment or radiation.
• Have received the following medications affecting the immune system within 14 days before entry: erythropoietin; Granulocyte Colony Stimulating Factor (G-CSF), including Granulocyte Macrophage Colony Stimulating Factors (GM-CSF); interleukins; or therapeutic HIV vaccines.