Immunomodulating Therapy and Improved Vaccination Responses by Cox-2 Inhibitor in HIV-infected Patients
Condition: HIV
Study type: Interventional
Phase: Phase 2

Summary: 
      Chronic immune activation is a central feature of HIV-infection, and the degree of activated
      T-cells is a better predictor of disease progression and mortality than plasma viral load.
      The study hypothesis is that the anti-inflammatory substance etoricoxib will dampen chronic
      immune activation and improve the effect of T-cell dependent vaccines in HIV-1 infected
      patients.

      The aim of the present study is to explore the efficacy of the study drug on markers of
      immune activation and vaccine responses, as well as safety of the study drug, in HIV-infected
      patients not receiving antiretroviral therapy and in patients on long-term effective ART who
      had CD4 counts < 500.
    

Detailed description: 
      The current trial was based on our observations that augmented levels of cyclic adenosine
      monophosphate (cAMP) contribute to the T cell dysfunction in HIV-infected patients. In T
      cells, cAMP triggers a protein kinase A (PKA) - Csk - Lck inhibitory pathway that inhibits
      the proximal T cell receptor (TCR) signaling events. This mechanism may also be involved in
      the inhibitory function of regulatory T cells.

      The investigators have hypothesized that elevated levels of cAMP in T cells from HIV-infected
      individuals result from increased production of prostaglandin E2 (PGE2) following
      activation-induced expression of cyclooxygenase type 2 (COX-2) in lymphoid tissues. Although
      the investigators have identified even COX-2 positive T cells in HIV-infected individuals,
      activated monocytes may be the major source of PGE2; high levels of COX-2 are produced de
      novo after a number of stimuli, particularly lipopolysaccharide (LPS). Circulating LPS is
      indeed increased in untreated chronic HIV infection due to enhanced translocation of
      microbial material and correlates to chronic immune activation and disease progression.

      In three preceding clinical explorative trials, the investigators have demonstrated that
      COX-2 inhibition by COX-2 inhibitors (COX-2i) improves the immune functions of HIV patients,
      the first two studies included patients on antiretroviral treatment (ART). In the third trial
      the investigators also showed for the first time that treatment with a COX-2i was able to
      downregulate chronic immune activation and improve T cell functions (efficacy of T
      cell-dependent vaccine) in asymptomatic HIV-infected patients who did not use ART. In these
      patients, chronic immune activation was dampened as demonstrated; CD38 density on CD8+ T
      cells (primary endpoint) decreased by 24% by study week 12. This reduction could be
      extrapolated to a possible improvement of CD4+ T cell loss with 30 CD4 cells per ul per year
      with an approximate mean CD4 loss of 60 per ul per year. These data founded the basis for
      further support to this study through the GLOBVAC call program under the Norwegian Research
      Council (granted application for the current study).
    

Intervention name(s): Etoricoxib
Intervention type(s): Drug
Intervention description(s): 90 mg QD
Other intervention name(s): Arcoxia
Intervention MeSH terms: Etoricoxib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cox-2 inhibitor; HIV; immune activation; immune modulating; progression markers; vaccine