Coincidentally, results from one of the IL-7 clinical trials mentioned in the prior post have just been published in the Journal of Clinical Investigation. Access to the full text of the paper is free of charge. The study reports that a short course of IL-7 treatment led to sustained increases in naïve and central memory CD4 and CD8 T cell levels out to 48 weeks of follow up. The primary mechanism of the increase appears to be increased proliferation of the cells; the researchers could not discern a contribution of increased thymic output, although they note that this could have been due to technical considerations. Limited data is presented on the functionality of the T cells; future studies will need to address this issue in more detail, perhaps by studying the impact on immune responses to routine immunizations (which was done previously with IL-2, showing no effect).
IL-7 treatment was well tolerated and clearly lacks the severe side effects associated with IL-2 administration. However, one individual in the higher dose group with a history of liver disease developed a grade 3 elevation in liver enzymes, necessitating cessation of treatment. Four out of seven individuals in the higher dose group also experienced transient viral load “blips,” which may relate to the reported ability of IL-7 to increase HIV replication in vitro. The number of infected cells – as assessed by measuring HIV proviral DNA – did not change as a result of IL-7 administration. Immune activation levels were also stable out to 12 weeks of follow up (48 week data is not reported). The researchers did not evaluate whether the CD4 T cell count changes induced by IL-7 had any impact on microbial translocation.
Overall, the data offer support for further evaluation of IL-7, particularly in individuals with low CD4 T cell counts despite viral suppression.
J Clin Invest. 2009 Mar 16. pii: 38052. doi: 10.1172/JCI38052. [Epub ahead of print]
Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelièvre JD, Boué F, Molina JM, Rouzioux C, Avettand-Fénoêl V, Croughs T, Beq S, Thiébaut R, Chêne G, Morre M, Delfraissy JF.
HIV infection results in CD4+ T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART-treated HIV-infected patients whose CD4+ cell counts were between 100 and 400 cells/mul and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 mug/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory CD4+ and CD8+ T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-gamma and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART.
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