Effects of Interleukin-2 Therapy
Effects of Interleukin-2 Therapy
Background: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients.
Methods: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550
10 cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5
10 IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74.
Results: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262
10 cells/l, respectively; P< 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls ( P< 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 ( P< 0.0001) and natural killer cells ( P< 0.001). In a logistic regression analysis, odds of being responders to recall antigens in vitro was 8.5-fold higher in IL-2 recipients ( P= 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01).
Conclusions: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone.
Administration of highly active antiretroviral treatment (HAART) combining different drugs including an HIV protease inhibitor (PI) has been successful in decreasing plasma viraemia to extremely low levels in a substantial proportion of HIV-infected patients. This has led to a significant improvement of the immune function and to a dramatic reduction in the incidence in both HIV-related mortality and AIDS-defining events. HAART is now the standard-of-care therapy in HIV infection. However, the extended use of HAART is not without drawbacks, including reduced adherence, toxic effects and viral resistance. Moreover, the ability of HAART to restore immunocompetence appears incomplete. Development of any complementary approaches, particularly those able to compensate for the limitations of HAART, would, therefore, be of interest.
Interleukin-2 (IL-2) is synthesized by CD4 T cells and has several immunomodulating effects, including the proliferation and differentiation of CD4 and CD8 T cells. Several clinical phase I/II studies have demonstrated that intermittent subcutaneous or continuous intravenous administration of IL-2 in HIV-infected patients induces a substantial expansion of CD4 T cells. These studies indicate that subcutaneous dosing is a convenient route of administration that minimizes drug-associated side effects and subsequently is manageable in an outpatient basis. A major concern with the use of IL-2 was the theoretical risk that this cytokine could stimulate HIV replication. However, randomized studies showed no significant increases in HIV RNA plasma levels in patients treated with IL-2. We and others have previously shown in patients treated with IL-2 a significant increase in naive and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and a trend toward a restoration of in vitro proliferative response to mitogens and recall antigens.
The present study reports the results of a multicentre, randomized controlled trial comparing the efficacy of subcutaneous IL-2 plus HAART with HAART alone in asymptomatic HIV-infected patients naive to antiviral treatment and/or to PI. The study examines the effect of the combination on plasma HIV RNA and whether IL-2 plus HAART might induce improved quantitative CD4 T cell counts and qualitative lymphocyte functions compared with HAART alone over 18 months of follow up.
Background: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients.
Methods: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550
10 cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5
10 IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74.
Results: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262
10 cells/l, respectively; P< 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls ( P< 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 ( P< 0.0001) and natural killer cells ( P< 0.001). In a logistic regression analysis, odds of being responders to recall antigens in vitro was 8.5-fold higher in IL-2 recipients ( P= 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01).
Conclusions: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone.
Administration of highly active antiretroviral treatment (HAART) combining different drugs including an HIV protease inhibitor (PI) has been successful in decreasing plasma viraemia to extremely low levels in a substantial proportion of HIV-infected patients. This has led to a significant improvement of the immune function and to a dramatic reduction in the incidence in both HIV-related mortality and AIDS-defining events. HAART is now the standard-of-care therapy in HIV infection. However, the extended use of HAART is not without drawbacks, including reduced adherence, toxic effects and viral resistance. Moreover, the ability of HAART to restore immunocompetence appears incomplete. Development of any complementary approaches, particularly those able to compensate for the limitations of HAART, would, therefore, be of interest.
Interleukin-2 (IL-2) is synthesized by CD4 T cells and has several immunomodulating effects, including the proliferation and differentiation of CD4 and CD8 T cells. Several clinical phase I/II studies have demonstrated that intermittent subcutaneous or continuous intravenous administration of IL-2 in HIV-infected patients induces a substantial expansion of CD4 T cells. These studies indicate that subcutaneous dosing is a convenient route of administration that minimizes drug-associated side effects and subsequently is manageable in an outpatient basis. A major concern with the use of IL-2 was the theoretical risk that this cytokine could stimulate HIV replication. However, randomized studies showed no significant increases in HIV RNA plasma levels in patients treated with IL-2. We and others have previously shown in patients treated with IL-2 a significant increase in naive and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and a trend toward a restoration of in vitro proliferative response to mitogens and recall antigens.
The present study reports the results of a multicentre, randomized controlled trial comparing the efficacy of subcutaneous IL-2 plus HAART with HAART alone in asymptomatic HIV-infected patients naive to antiviral treatment and/or to PI. The study examines the effect of the combination on plasma HIV RNA and whether IL-2 plus HAART might induce improved quantitative CD4 T cell counts and qualitative lymphocyte functions compared with HAART alone over 18 months of follow up.
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