Immunomodulating Therapy and Improved Vaccination Responses by Cox-2 Inhibitor in HIV-infected Patients

NCT ID: NCT01269515

Last Updated: 2017-05-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2014-11-30

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).

Conditions

HIV

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Etoricoxib 90 mg qd for 25 weeks ART-

Etoricoxib for 25 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 5 weeks.

Group Type: ACTIVE_COMPARATOR

Etoricoxib

Intervention Type: DRUG

90 mg QD

Etoricoxib 90 mg qd for 2 weeks ART-

Etoricoxib for 2 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

Group Type: ACTIVE_COMPARATOR

Etoricoxib

Intervention Type: DRUG

90 mg QD

Control ART-

No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Etoricoxib 90 mg qd for 25 weeks ART+

Etoricoxib for 25 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 5 weeks.

Group Type: ACTIVE_COMPARATOR

Etoricoxib

Intervention Type: DRUG

90 mg QD

Etoricoxib 90 mg qd for 2 weeks ART+

Etoricoxib for 2 weeks. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

Group Type: ACTIVE_COMPARATOR

Etoricoxib

Intervention Type: DRUG

90 mg QD

Control ART+

No Etoricoxib. Vaccination (Tetanus Toxoid, conjugated pneumococcal, seasonal influenza) after 1 week.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Etoricoxib

90 mg QD

Intervention Type: DRUG

Other Intervention Names

Arcoxia

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Research Council of Norway

OTHER

Sponsor Role: collaborator

Dag Kvale

OTHER

Sponsor Role: lead

Responsible Party

Dag Kvale

Professor, Senior consultant

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Dag Kvale, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Oslo University Hospital

Locations

Department of Infectious Diseases, Oslo University Hospital

Oslo, , Norway

The Biotechnology Centre, University of Oslo

Oslo, , Norway

Countries

Norway

References

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.

Reference Type: RESULT

PMID: 28464042 (View on PubMed)

Other Identifiers

OUSCOX2

Identifier Type: -

Identifier Source: org_study_id