Efficacy of Low‐Dose Intermittent Subcutaneous Interleukin (IL)–2 in Antiviral Drug–Experienced Human Immunodeficiency Virus–Infected Persons with Detectable Virus Load: A Controlled Study of 3 IL‐2 Regimens with Antiviral Drug Therapy

Abstract

To evaluate the safety and efficacy of 3 regimens of intermittent subcutaneous (sc) interleukin (IL)--2 in a phase 2 study, 61 antiviral drug-experienced human immunodeficiency virus (HIV)--positive patients were randomly assigned to one of the following study arms: antiretroviral therapy (ART) plus IL-2 (12 million IU [MIU] by continuous intravenous infusion, followed by 7.5 MIU twice a day, sc, every 8 weeks); ART plus IL-2 (7.5 MIU twice a day, sc, every 8 weeks); ART plus IL-2 (3 MIU twice a day, sc, every 4 weeks); or ART alone. A significant increase of circulating CD4 cells was observed in IL-2--treated subjects, compared with those given ART alone. Low doses of IL-2 were better tolerated. Despite the incomplete suppression of viral replication, IL-2 with ART did not increase either plasma viremia or cell-associated HIV DNA levels. Low doses of intermittent sc IL-2 induced a stable increase of peripheral CD4 cells that was indistinguishable from those associated with higher, less well-tolerated doses of IL-2.

Natural Regulatory T Cells and Persistent Viral Infection

“…However, if the primary role of IL-2 is to promote tolerance, the outcome of these trials may to some degree reflect the consequence of manipulating the Treg compartment. IL-2 therapy resulted in a sustained increase in CD4 T-cell counts for most patients (19,70,125), and the effect appeared to be long lasting as shown by 10-year follow-up studies (75). In a pooled retrospective analysis of IL-2 given intravenously, plasma HIV RNA levels were significantly lower in IL-2-treated patients than in patients receiving antiretroviral therapy only (32).…”

Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression

“…IL-2, a ␥c-cytokine activating STAT5, 4 is currently in a phase III efficacy trial as a potentially effective therapy in HIV disease based on its capacity to expand CD4 ϩ T lymphocytes without increasing viral load. [71][72][73][74] When we compared the impact of intermittent IL-2 administration on STAT5 activation in individuals who responded either well or poorly in terms of CD4 ϩ T cell count increase, we observed that STAT5⌬ activation was more prominent in the good versus the poor responder. 6 Like IL-2, GM-CSF is also currently being studied for its hematopoietic reconstitution capacity and as a potential adjuvant to antiretroviral therapy.…”

IL-7 is a potent and proviral strain–specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART

“…Several cytokines, including IL-2, IL-7, and IL-15, which share a common γ chain, might have putative roles in improving control of HIV-1 infection; of these, IL-2 is the best characterized (2)(3)(4). Although recombinant human IL-2 (rhIL-2) plus HAART produced significant CD4 + T lymphocyte expansion without an increase in viral load (5)(6)(7)(8), the effects of this combination on purging viral reservoirs is somewhat unclear (2,3).…”