Interleukin-2 with dual nucleoside therapy

Several studies are underway evaluating the effectiveness of interleukin-2 (IL-2) in HIV-infected patients. This medication has already been shown to be a potent stimulant of CD4+ T cells in patients on highly active antiretroviral therapy (HAART), but concerns remain regarding IL-2 stimulation of HIV replication in patients not on HAART and the effect of IL-2 on viral reservoirs.

In a report in AIDS, researchers from France reported the results of a study that evaluated the use of IL-2 in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) in 27 patients. The mean pretreatment CD4+ T cell count and viral load were 428 cells/mm3 and 17, 000 copies/mL. All patients were treated with 2 NRTIs and received 7 intermittent 5 day subcutaneous (4.5 MIU twice a day) or continuous intravenous (12 MIU/day) IL-2 cycles, every 8 weeks, during the first year. After the first year, subcutaneous IL-2 cycles were administered as needed to maintain the CD4 cell response. The median follow-up for these patients was 41 months.

During the follow-up period, 60% of the patients needed a median of 2 additional IL-2 cycles to maintain their CD4 cell response. In addition, 4 of 27 patients received highly active antiretroviral therapy (HAART). The mean CD4+ T cell count and viral load of the treated patients were 1052 cells/mm3 and 240 copies/mL at month 12 of treatment and 1016 cells/mm3 and 350 copies/mL at the last patient assessment. At the last assessment, 10 of 27 patients (37%) had a viral load <20 copies/mL.

In addition to significant immune recovery with this regimen, there were significant decreases in proviral DNA/106 peripheral blood mononuclear cells (PBMCs) indicating a decrease in the viral reservoir and that “long-term IL-2 may lead to a very low level of the pool of CD4 T cells harbouring replication-competent HIV.” Further, HIV-specific CD4 memory cells were also increased in these patients relative to a group of patients with comparable CD4+ T cell counts treated with HAART indicating that IL-2 therapy with NRTIs was superior to HAART in preserving virus-specific CD4+ effector T cells.

The authors conclude, “We show here that a ‘maintenance’ IL-2 regimen, with manageable toxicity, may lead to a sustained increase in CD4 T cell counts, preservation of HIV-specific immunity in patients, albeit treated only binucleosides.” While these data are clearly preliminary, and should not be the basis for any clinical decisions, they do indicate the multifaceted effectiveness of IL-2 in HIV-infected patients and support hope for the use of this agent to support and extend the immune system of HIV-infected patients.

Comment

The immunological outcomes of IL-2 administration confirmed by this study are now well established. Of note with this particular cohort however, is the remarkable degree of virological control maintained despite the use of “sub-optimal” dual nucleoside therapy. Mean plasma HIV-RNA level was 17, 000 copies/mL for the cohort was 17, 000 copies/mL before any treatment. At one year it would appear that approximately 50% of patients had VL <500 copies/mL and by the end of the first year of extended follow-up the mean plasma VL was 240 copies/mL. At the last assessment (median follow-up three-and-a-half years) 10/27 patients had plasma VL less than 20 copies/mL indicating that HIV viraemia was well controlled over an extended period despite treatment with a less than optimal antiviral regimen.

It is hypothesised that antiretroviral HIV suppression may allow autologous antigenic stimulation of HIV-specific CD4 and CTL responses which may be boosted by the IL-2 administration. Anti-HIV host immunity may then contribute to the maintenance of virologic control.