Immunomodulating Therapy and Improved Vaccination Responses by Cox-2 Inhibitor in HIV-infected Patients (OUSCOX2)
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Optional Immunomodulating Therapy and Improved Vaccination Responses by Adjuvant Administration of a Cyclooxygenase Type 2 Inhibitor in Antiretroviral naïve HIV-infected Patients|
- Changes in progression markers and vaccine responses [ Time Frame: After 6 months ] [ Designated as safety issue: No ]Changes in CD38 density (CD38 molecules per CD38+CD8+CD3+ T cells) and in humoral and cellular immune responses to study-specific vaccines.
- Serious adverse events [ Time Frame: During the 6 months study period ] [ Designated as safety issue: Yes ]Reductions of etoricoxib dose or stop of drug, adverse events including cardiovascular events, blood pressure, clinical chemistry.
- Changes in progression markers [ Time Frame: 6 months ] [ Designated as safety issue: No ]Changes in CD38 density (molecules/cell) in CD8+PD-1+ or other T cell subsets, CD4+ T cell counts, HIV RNA, immunoglobulin levels, β2-microglobulin, CRP, D-dimer.
- Clinical events [ Time Frame: 6 months ] [ Designated as safety issue: No ]HIV-related clinical events, Indication for antiretroviral treatment.
|Study Start Date:||October 2010|
|Estimated Study Completion Date:||December 2012|
|Estimated Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Active Comparator: Etoricoxib 90 mg qd for 25 weeks
Etoricoxib for 25 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 5 weeks.
90 mg QD
Other Name: Arcoxia
Active Comparator: Etoricoxib 90 mg qd for 2 weeks
Etoricoxib for 2 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.
90 mg QD
Other Name: Arcoxia
No Intervention: Control
No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.
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).
|Department of Infectious Diseases, Oslo University Hospital||Recruiting|
|Oslo, Norway, 0407|
|Contact: Dag Kvale, MD, PhD +4795200709 email@example.com|
|Principal Investigator: Dag Kvale, MD, PhD|
|The Biotechnology Centre, University of Oslo||Recruiting|
|Oslo, Norway, 0407|
|Contact: Kjetil Tasken, MD, PhD +4790860759 firstname.lastname@example.org|
|Principal Investigator: Kjetil Tasken, MD, PhD|
|Principal Investigator:||Dag Kvale, MD, PhD||Oslo University Hospital|