Effect of Interleukin-2 on HIV Treatment Interruption

An Open-Label, Pilot Study Utilizing CD4 T-Cell Counts Lower Than 350 Cells/mm3 as the Threshold for Restarting Therapy With Potent Antiretroviral Therapy With or Without Interleukin-2 to Determine the Effect of Pulse Therapy on the Characteristics of Treatment Interruptions

Interleukin-2 (IL-2) helps the body make infection-fighting white blood cells, including CD4 and CD8 T cells. One HIV treatment strategy is planned treatment interruption (stopping anti-HIV drugs when CD4 count and level of virus in the blood are at certain levels). The purpose of this study is to see if IL-2 used with potent anti-HIV drugs allows for longer HIV treatment interruptions.

One approach in reconstituting an HIV-diminished immune system is the use of potent antiretroviral therapy (ART) in conjunction with IL-2. IL-2 is a cytokine secreted by activated T cells that regulates the proliferation and differentiation of CD4 and CD8 T cells. Although treatment with IL-2 can cause temporary increases in HIV viral load, clinical studies with IL-2 have revealed no long-term adverse effects on viral load. IL-2 therapy may also help purge the host's latent viral reservoir through activation of resting lymphocytes harboring provirus. Another approach to managing HIV infection is strategic treatment interruption. Results from small pilot trials suggest that HIV replication can be highly suppressed over consecutive courses of ART following short treatment interruptions, and CD4 T cell counts can be maintained on these interruptions with some positive effect on HIV-specific immunity. This study will evaluate potent ART, started and interrupted based on CD4 cell counts, with or without IL-2. Patients will be stratified based on lifetime CD4 T-cell nadir (lowest measurement) into one of three groups. Group 1 will have a nadir of 200 CD4 cells/mm3; Group 2 will have a nadir greater than 200 CD4 cells/mm3; and patients with no documented nadir count available will join Group 3. Within each group, patients will be randomly assigned to one of two study arms. Arm A patients will receive pulses of potent ART with IL-2, while Arm B patients will receive pulses of potent ART alone. Patients in Arm A will receive potent ART with IL-2 given by subcutaneous injection twice daily for 5 days every 8 weeks for at least 17 weeks. Arm B patients will receive potent ART alone for at least 17 weeks. Both groups then go on treatment interruption for approximately 64 weeks, followed by potent ART alone for an additional 24 weeks. Patients will repeat this cycle of potent ART with or without IL-2, treatment interruption, and potent ART alone throughout the study. This study will last approximately 4 years. Clinical and laboratory assessments will be performed periodically throughout the study. CD4 T cell counts and viral load will determine if a patient can enter the next treatment step. Potent ART is not provided by this study. A5109s is a limited-center substudy designed to determine whether viral replication impairs lymphocyte proliferation in vivo. Patients at substudy-participating sites will register to the substudy immediately after beginning their first treatment interruption in the main study.

Treatment Experienced, Treatment Interruption, Drug Administration Schedule, CD4 Lymphocyte Count, Anti-HIV Agents, Tetanus Toxoid, Aldesleukin, Diphtheria Toxoid

Inclusion Criteria: HIV infected On stable, potent ART regimen for at least 3 months prior to study entry Viral load of less than 400 copies/ml for at least 6 months prior to study entry Viral load of less than 200 copies/ml at screening CD4 count of 500 cells/mm3 or greater at screening Agree to use acceptable methods of contraception Agree to be followed on this study for at least 4 years Primary care provider willing to have the patient in the study and to comply with study guidelines Exclusion Criteria: Active or past significant AIDS-related illness. Patients with a history of minimal (less than 10 lesions) cutaneous Kaposi's sarcoma, pulmonary tuberculosis, or bacterial pneumonia are not excluded. Immunomodulators within 1 month of study entry Hydroxyurea within 3 months of study entry Prior IL-2 treatment Drugs to treat heart disease within 30 days of study entry Serious heart problems Cancer requiring anti-cancer drugs Thyroid problems. If the condition has been controlled by drugs for at least 3 months prior to study entry, the patient is not excluded. Uncontrolled diabetes Breathing or stomach problems that, in the opinion of the investigator, may affect the safety of the patient History of autoimmune disease, including inflammatory bowel disease, psoriasis, and optic neuritis Organ transplant History of neurological disorder or mental illness that, in the opinion of the investigator, may interfere with study requirements Alcohol or drug abuse that, in the opinion of the investigator, may interfere with study requirements Astemizole, midazolam, or triazolam within 2 weeks of study entry Systemic corticosteroids for 4 weeks or more within 3 months of study entry Pregnancy or breastfeeding

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