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IL-7 Increased T-Cells CD4/CD8/Naive/Memory:
In HIV, Cytokine Boosts Immune System
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MedPage Today
March 17, 2009
CRETEIL, France, March 17 -- For HIV patients with suppressed immune systems, adding interleukin-7 to combination therapy increased the number of immune cells, researchers here said.
Action Points
* Explain to interested patients that although most HIV patients respond to combination antiretroviral therapy with a robust restoration of the immune system, some do not.
* Note that this small study suggests that the cytokine interleukin-7 can cause significant increases in immune cells, although more research is needed.
In a small, open-label phase I/IIa trial, the cytokine was well tolerated and induced a sustained increase in both naive and memory T cells, according to Yves Levy, M.D., of Hopital Henri Mondor, and colleagues.
The finding is important because a low immune cell count is associated with poorer outcomes, even if the virus itself is well controlled, the researchers reported online in the Journal of Clinical Investigation.
It also comes after two large phase III trials (one led by Dr. Levy) showed that another cytokine, interleukin-2, did not improve outcomes in HIV. (See: CROI: IL-2 Benefit in HIV Ruled Out)
Mounting evidence suggests that the length of time patients spend with a low CD4-positive T cell count is associated with higher morbidity, the researchers said.
"A new frontier in HIV therapy may be defined by the maintenance of a high level of CD4-positive T cells," they said.
Controlling the virus itself is an "attainable goal," the researchers said, but although most patients respond to combination antiretroviral therapy with a robust recovery of immune function, some do not.
To test the impact of interleukin-7, the researchers enrolled 14 patients with plasma HIV RNA levels less than 50 copies per milliliter and CD4 cell counts of between 100 and 400 cells per microliter.
Patients were given subcutaneous injections of recombinant human interleukin-7 every second day for 16 days, at one of two doses -- six patients got three micrograms per kilogram of body weight, and eight patients got 10 micrograms per kilogram.
All patients in the low-dose group got all eight injections, but one patient in the high-dose group did not get the eighth shot because of dose-limiting toxicity, and another patient got only a single injection. All patients completed up to 48 weeks of follow-up.
The cytokine induced significant increases in immune cell counts that were sustained throughout the 48 weeks of follow-up, the researchers reported. Specifically:
* At 28 days, those in the low-dose group had a median gain of 118 CD4 cells (a 68% increase over baseline) and those in the high-dose group had a median gain of 576 cells (a 212% increase). The increases were significant at P=0.03 and P=0.02, respectively.
* At 12 weeks, median CD4 counts were 54% higher than baseline in the low-dose group and 130% higher than baseline in the high-dose patients. Both differences were significant at P<0.0001.
* At 48 weeks, median CD4 counts were 28% higher than baseline in the low-dose group and 75% higher than baseline in the high-dose patients. Both differences were again significant at P<0.0001.
A similiar pattern was seen for CD8-positive T cells, the researchers said. The expanded CD4-positive and CD8-positive T cells remained functional and responded in vitro to TCR stimulation and produced intracellur cytokines after polyclonal and antigen-specific stimulation.
Administration of the cytokine was well tolerated, with transient and mild to moderate injection site reactions.
One patient in the high-dose group had a grade three increase in liver function enzymes, but aside from that no grade 3 or 4 adverse events were seen, the researchers said.
Dr. Levy and colleagues said new formulations of the cytokine now under development could allow an "optimized" therapeutic strategy that would be more convenient for patients.
They noted that a randomized controlled trial is needed to demonstrate the clinical benefits of interleukin-7.
They noted that "One possible limitation of the use of IL-7 in HIV setting was raised by experimental data showing that IL-7 may enhance HIV replication. "In this study, in the highest dose group, four patients experienced transient increase in viral replication.
The researches pointed out that "these results underscore the importance of carefully monitoring viral load in future randomized studies".
The researchers did not report support for the study.
Two of the authors are employees of Cytheris S.A., a French company developing immune-enhancing therapies.
Dr. Levy reported no conflicts.
Primary source: Journal of Clinical Investigation
Source reference:
Levy Y, et al "Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment" J Clin Invest 2009; DOI: 10.1172/JCI38052.
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