HIV infection activates the immune system. This is a normal response to a viral infection. However, because the immune system is usually unable to rid itself of HIV, immune activation persists, even with the use of potent combination anti-HIV therapy, commonly called ART or HAART. Prolonged immune activation can cause chronic inflammation, which can slowly degrade vital organ-systems. This may be why HIV-positive people are at increased risk for premature cardiovascular disease, thinning bones, kidney dysfunction and other complications associated with aging.
Researchers are testing different therapies to try and reduce excessive immune activation in HIV-positive people. One drug with the potential to reduce immune activation is celecoxib (Celebrex). This drug belongs to a class of anti-inflammatory agents called COX-2 inhibitors.
Researchers in Norway conducted a randomized pilot study to test the effectiveness of celecoxib in HIV-positive people who were not taking ART. They found that participants who took 800 mg of celecoxib each day had a modest reduction in immune activation and inflammation. Improvements in the functioning of their T-cells were also modest.
Study details
Researchers at Oslo University Hospital recruited HIV-positive people who were not taking any of the following medications:
- ART
- non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen (Advil, Motrin)
- corticosteroids
- interferon-alpha
Since some COX-2 inhibitors have previously been associated with an increased risk for heart attack and stroke, researchers decided to exclude from the study people who had cardiovascular disease (CVD) or risk factors for CVD, including the following:
- higher than normal blood pressure
- kidney dysfunction
- diabetes
- stroke, heart attack or peripheral artery disease
- close family members (parents or siblings) who had a heart attack or stroke before the age of 55
- liver injury
Participants were randomly assigned to one of two groups. They were given either:
- high-dose celexocib – 400 mg twice daily for 12 consecutive weeks; or
- no celexocib.
Participants were interviewed and examined four weeks prior to taking celecoxib and again six weeks after they stopped taking it. Blood and urine samples were taken at the start and end of the study.
In total, 31 participants were enrolled in the study. Of those, 17 received celecoxib and 14 received no drug. The average profile of participants at the start of the study was as follows:
- age – 40 years
- length of time HIV-positive – 2.5 years
- CD4+ count – 425 cells
- CD8+ count – 1200 cells
- viral load – 40,000 copies/ml
Results
Immune activation
The main purpose of the study was to assess changes in immune activation as a result of taking celecoxib. To do this, technicians tested blood samples for levels of the protein, or marker, CD38 because activated cells tend to express CD38. When researchers specifically assessed CD8+ cells for CD38, they found that the levels of CD8+ cells expressing this marker among people who received celecoxib fell by 25% compared to pre-study levels. This decrease was statistically significant.
In contrast, the levels of CD8+ cells expressing CD38 among people who did not take celecoxib increased by about 4%.
There were no significant changes in CD4+ T-cells that displayed CD38 in either group of participants.
HIV infection appears to excessively stimulate the part of the immune system that produces antibodies—B-cells. Despite this stimulation, the vast majority of HIV-positive people are unable to fully suppress HIV's ability to damage their immune system. Also, by over-stimulating B-cells, HIV infection may increase the risk of such cells transforming into pre-cancerous growths and, in some cases, cancers. It is likely that through this, and possibly other mechanisms, HIV infection increases the risk of B-cells forming cancers called lymphoma.
In the Norwegian study, researchers found that levels of a group of antibodies called IgA—generally produced in mucosal tissues—were significantly reduced.
Viral load and T-cells
The HIV viral load of participants who received celecoxib remained stable but the viral load of participants who did not receive the drug increased by 10,000 copies/ml.
The levels of CD4+ and CD8+ T-cells remained stable in all participants.
With HIV infection, some cells of the immune system, particularly T-cells not infected by HIV, are at increased risk for undergoing self-destruction. This process of auto-destruction is called apoptosis. The CD8+ cells from celecoxib recipients appeared to be less likely to have been preparing for apoptosis. Also, those who were taking celecoxib had T-cells that seemed less dysfunctional than before they received the drug. Whether these T-cells rescued by exposure to celecoxib are able to directly control HIV or attack tumours was not assessed in this study.
Blood clots
When levels of a protein called D-dimer increase in the blood, this suggests that blood clots are more likely to form. Such clots can become larger and block vital blood vessels, leading to an increased risk for heart attack or stroke. D-dimer levels did not rise among people given celecoxib but did increase among people who did not take this drug.
Vaccines
A subgroup of participants also received vaccinations for tetanus and pneumonia (both vaccines were made by Sanofi Pasteur). Although antibody levels to tetanus increased among all receipients, they did so more significantly among celecoxib recipients.
In contrast, when given the pneumonia vaccine, celecoxib recipients had their antibody levels rise modestly (about 50%) but participants who did not receive celecoxib had their antibody levels rise by nearly 350%.
Adverse effects
Four participants who received celecoxib developed a widespread itchy and bumpy rash on their bodies within two weeks of starting this drug. In one person, the rash resolved spontaneously but in three others, antihistamines or corticosteroids were needed to provide relief. They also had to stop taking the drug. Blood tests suggested that these four participants had a greater degree of immune activation than other participants.
A long time ago
Since the beginning of the HIV pandemic, some researchers have theorized that low-level infection with harmful bacteria, parasites or viruses, in addition to HIV infection, may stimulate the immune system to produce chemicals that cause the immune system to become increasingly dysfunctional. One chemical with this potential is called PGE 2 (prostaglandin E 2 ). Before ART became widely available in high-income countries, some researchers tested anti-inflammatory drugs, such as indomethacin and aspirin, in the hope of reversing HIV-related immune dysfunction. However, such drugs did not have a sustained impact and were not able to prevent life-threatening infections associated with AIDS.
Concerns about safety
COX-2 inhibitors became available in the late 1990s and, by virtue of their selective anti-inflammatory effects, may have the potential to partly reverse some of the immunologic defects resulting from HIV infection. However, COX-2 inhibitors belong to a class of medicines that has had its share of troubles. At least one drug in this class (Vioxx) has been withdrawn from sale because of concerns about increased risk of heart attack. Some studies suggest that exposure to celecoxib seems relatively safe, while other studies have found an increased risk for cardiovascular complications such as stroke. Also, because of warnings about other COX-2 inhibitors, doctors may now be more cautious about prescribing this drug. Quebec researchers have found that, compared to 10 years ago, the patients who are prescribed COX-2 inhibitors nowadays tend not to be as seriously ill.
Still, because HIV-positive people appear to be at increased risk for premature cardiovascular disease, some doctors may be cautious about the use of COX-2 inhibitors in this population.
Other attempts
Celecoxib is not the only drug being tested for its potential to help reduce excessive inflammation in HIV-positive people. A double-blind, placebo-controlled study of the lipid-lowering medicine atorvastatin (Lipitor) has also been conducted in HIV-positive HAART users. Researchers found a very modest reduction in the level of immune activation among participants who took atorvastatin.
In perspective
The data from Norway suggest that celecoxib has the potential to reduce HIV-related immune activation in people not taking ART over the short-term. In a previous study, also conducted in Norway, researchers tested celecoxib for six months in volunteers who used ART. In this group, celecoxib helped reduce immune activation. Also, CD4+ cell counts increased among participants whose viral load was less than 50 copies/ml. It is worth noting that in this study, a 41-year old man who received celecoxib died suddenly and unexpectedly. Autopsy results suggested that the blood vessels to his heart were prematurely narrowed. Investigators suspected that exposure to celecoxib was related to his death.
Atorvastatin and celecoxib can modestly reduce immune activation in HIV-positive people. A clinical trial to assess how such changes might impact the health of HIV-positive people over the long-term would require at least hundreds of volunteers and would need to proceed for several years. This is an expensive prospect for drugs with possibly modest benefit and, in the case of high-dose celecoxib, the potential for toxicity in people with risk factors for cardiovascular disease.
—Sean R. Hosein
REFERENCES:
- Chougnet CA, Margolis D, Landay AL, et al. Contribution of prostaglandin E 2 to the interleukin-12 defect in HIV-infected patients. AIDS . 1996 Aug;10(9):1043-5
- Macilwain C. Aspirin on trial as HIV treatment. Nature . 1993 Jul 29;364(6436):369.
- Bourinbaiar AS, Lee-Huang S. The non-steroidal anti-inflammatory drug, indomethacin, as an inhibitor of HIV replication. Federation of European Biochemical Societies Letters . 1995 Feb 20;360(1):85-8.
- Vang T, Torgersen KM, Sundvold V, et al. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. Journal of Experimental Medicine. 2001 Feb 19;193(4):497-507.
- Anwar K, Voloshyna I, Littlefield MJ, et al. COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells. Lipids . 2011 Feb;46(2):131-42.
- Rahme E, Roussy JP, Lafrance JP, et al. Use of nonsteroidal antiinflammatory drugs: is there a change in patient risk profile after withdrawal of rofecoxib? Journal of Rheumatology . 2011 Feb;38(2):195-202.
- Vaithianathan R, Hockey PM, Moore TJ, et al. Iatrogenic effects of COX-2 inhibitors in the US population: findings from the Medical Expenditure Panel Survey. Drug Safety . 2009;32(4):335-43.
- Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation . 2008 Apr 22;117(16):2104-13.
- Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ . 2011 Jan 11;342:c7086.
- Kvale D, Ormaasen V, Kran AM, et al. 1. Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment. AIDS . 2006 Apr 4;20(6):813-20.
- Pettersen FO, Torheim EA, Dahm AE, et al. An Exploratory Trial of Cyclooxygenase Type 2 Inhibitor in HIV-1 Infection: Downregulated immune activation and improved T cell-dependent vaccine responses. Journal of Virology . 2011 Jul;85(13):6557-66.
- De Wit S, Delforge M, Necsoi CV, et al. Downregulation of CD38 activation markers by atorvastatin in HIV patients with undetectable viral load. AIDS . 2011 Jun 19;25(10):1332-3.
- Ganesan A, Crum-Cianflone N, Higgins J, et al. High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial. Journal of Infectious Diseases . 2011 Mar 15;203(6):756-64
From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE
