Clinical trial NCT01269515: Immunomodulating Therapy and Improved Vaccination Responses by Cox-2 Inhibitor in HIV-infected Patients
Official title: Optional Immunomodulating Therapy and Improved Vaccination Responses by Adjuvant Administration of a Cyclooxygenase Type 2 Inhibitor in Antiretroviral naïve HIV-infected Patients and Patients on ART
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV
Keywords: Cox-2 inhibitor
HIV
immune activation
immune modulating
progression markers
vaccine
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
First posted: 2011-01-04
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Eligibility criteria: Inclusion Criteria:

ART- group: Confirmed diagnosis of HIV infection \< 8 years prestudy

* no HIV-related clinical manifestations including acute HIV infection
* no current indication or use for antiretroviral treatment
* CD4+ count \> 350 x 10\^6 /l
* HIV RNA \> 2000 copies/ml

ART+ group: Confirmed diagnosis of HIV infection

* no HIV-related clinical manifestations including acute HIV infection
* On stabile effective antiretroviral treatment (HIV RNA \<50 copies/ml)
* CD4+ count \< 500 x 10\^6 /l
* HIV RNA \> 2000 copies/ml

Exclusion Criteria:

* concomitant or sporadic use of NSAID, corticosteroids or other immune modulating therapies including interferon-alpha
* cholesterol \> 7 M
* under treatment for hypertension or antihypertensive treatment indicated at inclusion
* cardiovascular events or stroke in parents, siblings or off-springs occurring \< 55 years of age
* elevated serum creatinine
* diabetes type I or II
* known hypersensitivity for etoricoxib, capsule substances or sulphonamides
* active peptic ulcer or gastrointestinal haemorrhage
* history of asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic reactions after taking acetyl salicylic acid or NSAID including COX-2 inhibitors
* pregnancy or insufficient birth control for females
* breastfeeding
* seriously deranged liver function
* creatine clearance \< 30 ml/min
* inflammatory bowel disease
* heart failure (NYHA II-IV)
* established ischaemic heart disease, peripheral arteriosclerosis and/or cerebrovascular disease

Primary outcomes:
measure: Changes in progression markers and vaccine responses within and between ART groups
timeFrame: After 6 months
measure: Serious adverse events
timeFrame: During the 6 months study period
Secondary outcomes:
measure: Changes in HIV Gag CD8+ T cell responses within and between ART groups
timeFrame: 6 months
measure: Changes in plasma markers of inflammation, coagulation and tryptophan metabolism within and between ART groups
timeFrame: 6 months
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Department of Infectious Diseases, Oslo University Hospital
city: Oslo
country: Norway
facility: The Biotechnology Centre, University of Oslo
Study officials:
affiliation: Oslo University Hospital
name: Dag Kvale, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prebensen C, Troseid M, Ueland T, Dahm A, Sandset PM, Aaberge I, Waalen K, Dyrhol-Riise AM, Tasken K, Kvale D. Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial. PLoS One. 2017 May 2;12(5):e0176527. doi: 10.1371/journal.pone.0176527. eCollection 2017.