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Stat Med. 2019 Jan 30;38(2):221-235. doi: 10.1002/sim.7957. Epub 2018 Sep 26.

Adaptive protocols based on predictions from a mechanistic model of the effect of IL7 on CD4 counts.

Villain L1,2,3, Commenges D1,2,3, Pasin C1,2,3, Prague M1,2,3, Thiébaut R1,2,3.

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University of Bordeaux, Inserm, Bordeaux, Population Health Research Center, Team SISTM, Bordeaux, France.
INRIA Bordeaux Sud Ouest, Talence, France.
Vaccine Research Institute (VRI), Hôpital Henri Mondor, Créteil, France.


In human immunodeficiency virus-infected patients, antiretroviral therapy suppresses the viral replication, which is followed in most patients by a restoration of CD4+ T cells pool. For patients who fail to do so, repeated injections of exogenous interleukin 7 (IL7) are experimented. The IL7 is a cytokine that is involved in the T cell homeostasis and the INSPIRE study has shown that injections of IL7 induced a proliferation of CD4+ T cells. Phase I/II INSPIRE 2 and 3 studies have evaluated a protocol in which a first cycle of three IL7 injections is followed by a new cycle at each visit when the patient has less than 550 CD4 cells/μL. Restoration of the CD4 concentration has been demonstrated, but the long-term best adaptive protocol is yet to be determined. A mechanistic model of the evolution of CD4 after IL7 injections has been developed, which is based on a system of ordinary differential equations and includes random effects. Based on the estimation of this model, we use a Bayesian approach to forecast the dynamics of CD4 in new patients. We propose four prediction-based adaptive protocols of injections to minimize the time spent under 500 CD4 cells/μL for each patient, without increasing the number of injections received too much. We show that our protocols significantly reduce the time spent under 500 CD4 over a period of two years, without increasing the number of injections. These protocols have the potential to increase the efficiency of this therapy.


HIV; adaptive protocols; interleukine 7; mechanistic models


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