Pilot Opened Trial in HIV-infected Patients Including an Investigational Marketed Product
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      This study aims to provide new knowledge about the pathogenesis of HIV infection,
      specifically, the role that immune activation and apoptotic activity play in immune recovery,
      and in particular, in the paradoxical immunologic response of some patients on antiretroviral
      therapy despite achievement of sustained and complete viral suppression. In this regard, the
      investigators will prospectively evaluate the impact of intensification with Raltegravir in
      those "discordants" patients with high index of immune activation, measured as the percentage
      of CD8+HLADR+CD38+ cells. This will provide relevant information on the effectiveness of this
      drug in guided intensification regimens.
    

Detailed description: 
      One of the many adverse consequences of the human immunodeficiency virus (HIV) infection is
      the increase in the rate of lymphocyte cell death (Badley AD, Blood. 2000; 96:2951-64).
      Increased lymphocyte death is associated with the level of activation of the immune system
      (Gougeon ML. Nat Rev Immunol. 2003: 3:392-404), along with the disregulation of the cytokine
      network and a plethora of cytotoxic effects induced by HIV proteins (Badley AD, Blood. 2000;
      96:2951-64). Hence, cell death can be observed in vivo not only in CD4+ cells, which are the
      main target of HIV, but also in CD8 T cells. Current knowledge suggest that immune activation
      and different mechanisms of cell death play a determinant role in T-lymphocyte (CD4+) loss
      during HIV infection and recovery after HAART (Bofill M et al AIDS. 1996 :827-34).

      Highly active antiretroviral treatment (HAART) induces a decline in the level of immune
      activation and lymphocyte apoptosis in HIV-infected patients as a result of a reduction in
      viral replication (Kolber MA, et al, Clin Immunol. 2007 [Epub ahead of print]). This
      reduction contributes to the recovery of immune system associated with antiretroviral
      therapy. In addition to this effect, which is induced through the reduction in viral load,
      antiretroviral therapy has been implicated in the regulation of apoptosis in different cell
      types, inhibiting or activating the process and influencing treatment efficacy and toxicity
      (Petit F, et al.Trends Pharmacol Sci. 2005. 26:258-64).

      Interestingly, it is not always true that antiretroviral therapy and viral suppression are
      associated with progressive immune recovery. Approximately 30% of patients present a
      paradoxical response to treatment, achieving progressive increases in immunity (measured by
      CD4+ count) despite failing to achieve viral suppression, or, vice versa, patients who
      maintain or reduce CD4+ cell count despite achieving viral suppression. Indeed, it is well
      known that higher CD8 activation is associated with fewer treatment-mediated CD4 gain. Each
      10% increase in activated CD8+HLADR+CD38+ mean 90 fewer CD4 cell gained (Hunt PW et al J
      Infect Dis. 2003. 187:1534-43). The failure of recover CD4 T cells may rely on a incomplete
      viral suppression than could be responsible for increased immune activation and lymphocyte
      death. Recently, it has been pointed out that intensification strategies may be useful in
      reducing activation and improving CD4 T cell recovery (Kolber MA, et al, Clin Immunol. 2007
      [Epub ahead of print]).
    

Intervention name(s): raltegravir
Intervention type(s): Drug
Intervention description(s): intensify their therapy with Raltegravir(RAL):1 Protease inhibitor plus 2 nucleoside reverse transcriptase inhibitor plus RAL or 1 non-nucleoside reverse transcriptase inhibitor plus 2 nucleoside reverse transcriptase inhibitor plus RAL
Other intervention name(s): N/P.
Intervention MeSH terms: Raltegravir Potassium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV infection; Discordant patient; CD4 recovery; intensification antiretroviral therapy; raltegravir; HIV-1 infected patient classified as "discordant" who showed high level of CD8+HLADR+CD38+ and cell death values at the screening