Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02898896 |
| Other study ID # |
9642 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2017 |
| Est. completion date |
January 5, 2018 |
Study information
| Verified date |
August 2019 |
| Source |
University Hospital, Montpellier |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
HIV-infected patients with intermediate-high risk have a high prevalence of CAD and a
substantial proportion of obstructive CAD. Degree of stenosis is associated with
immunoactivation (lymphocyte and monocyte) and microbial translocation
Description:
A hallmark of HIV infection is a state of global immune activation that is only partially
restored under highly active antiretroviral therapy. Apart from immune deficiency and
impaired immune restoration, this chronic immune activation may result via various mechanisms
in non-AIDS linked morbidities such as atherosclerosis. Coronary artery disease (CAD),
especially myocardial infarction (MI), is the leading cause of death in Europe [Eurostat
2013]. Cardiovascular deaths are responsible for 8% of deaths among HIV-infected patients in
France and for 15% of deaths among HIV-infected patients in US [Lewden C JAIDS 08, Palella FJ
JAIDS 06]. Multiple cohort studies have shown that HIV-infected patients are at a higher risk
of myocardial infarction than the general population [Triant VA J Clin Endocrinol 07,
Freiberg MS JAMA Intern Med 13] and there is some evidence that HIV-infected patients have a
38% greater risk of mortality from MI than controls [Pearce D AM J Cardiol 12].
Several tools for cardiovascular risk stratification are available but current risk scores
seem to underestimate this risk in HIV-infected patients. Indeed, a significant proportion of
cardiovascular events occur in subjects with none or few risk factors. A European study
comparing first episode of MI among HIV-infected patients with uninfected controls showed
that 40% had none or only one traditional cardiovascular risk factor [Boccara F Eur Heart J
11]. Another study in general population demonstrates that almost 50% of patients with a MI
had no previous history of coronary symptoms [Tunstall-Pedoe H Circulation 96].
The true prevalence of CAD in asymptomatic HIV-infected patients is unknown. Older studies
performed in tissue samples from deceased patients demonstrated 3-times greater odds of
having obstructive CAD in HIV-infected patients compared with non-infected controls after
controlling for age and sex [Micheletti RG Cardiovasc Pathol 09]. A recent meta-analysis
shows that the prevalence of coronary stenosis and calcified coronary plaques is similar in
comparison with non-HIV age and sex-matched controls but HIV-infected patients have a 3-fold
higher prevalence of non-calcified coronary plaques [D'Ascenzo Atherosclerosis 15].
CAD severity detected by coronary computed tomographic angiography (CCTA) is associated with
cardiac death or MI and all-cause mortality [Habib F Int J Cardiol 12]. 64 slice or greater
CCTA is reported to have a sensitivity of 93 to 97% and specificity of 80 to 90% compared to
standard coronary angiography [Fihn SD J Am Coll Cardiol 12]. There is a high correlation
between CCTA and invasive coronary angiography in the determination of CAD extent and
severity [Miller JM N Engl J Med 08].
Whether routine CCTA screening in high-risk populations can effect changes in treatment (such
as pre-emptive coronary revascularization or more aggressive medical therapy) remains
unproven. The 2013 AHA guidelines about stable ischemic heart disease states that either
stress test or anatomic imaging in higher-risk individuals may be appropriate [J Am Coll
Cardiol 14].
Few studies using CCTA have been performed in HIV-infected patients and none of these have
been done in intermediate-high risk populations. Most of theses studies have shown an
increased prevalence of non-calcified plaques in HIV-infected men (59% vs. 34%) compared with
controls non infected with similar CVRF [Lo J AIDS 10, Post W Ann Intern Med 14]. There is
some inconsistent data regarding clinical variables associated with coronary stenosis.
Meanwhile CD4 nadir, use or ART for more than 10 years and detectable viral load were
independently associated with coronary stenosis > 50% in the MACS cohort study [Post W Ann
Intern Med 14], another study among African-Americans with HIV only cardiovascular risk
factors and cocaine use were associated with coronary stenosis [Lai S Clin Infec Dis 08]
Although the epidemiology and pathogenesis of HIV associated cardiovascular disease are
complex and controversial we know that the risk of cardiovascular events is higher in
untreated than treated HIV infection, probably because inflammation is increased in untreated
infection. Recent data have raised interest in the role of Monocytes/macrophages in
HIV-associated cardiovascular disease. Increased levels of monocytes activation markers such
as sCD14 and sCD163 are associated with increased all-cause mortality and HIV progression, as
well as more rapid progression of carotid atherosclerosis, aortic inflammation and
non-calcified coronary plaque [Kelesidis JID 12, Subramanian S, JAMA 12, Burdo JID 11]. There
is some evidence that monocyte profile in untreated HIV infection mirrors those with acute
coronary syndrome [Funderberg N Blood 12] and circulating monocytes CD16+ were associated
with coronary artery calcium progression in the SUN cohort [Baker AIDS 14]. Data from the
MACS cohort showed that elevated levels of monocyte activation markers (sCD163, sCD14 and
CCL2) in HIV-infected men were associated with CAC and coronary artery stenosis [Mc Kibben RA
J Infec Dis 15]. None of these studies have been performed in cardiovascular high-risk
virologically suppressed patients.
HIV infection causes dramatic damage to the gastrointestinal (GI) tract that includes
substantial disruption of gut microbiota composition with presence of microbes at higher
pathogenic potential compared to less agressive indigenous organisms, and massive loss of
gut-residing CD4+ T-cells (Brenchley NAT MED 2006, Gori J Clin Microbiol 2007, Douek Annu Rev
Med 2009). Thus, a substantial breach of the anatomo-functional GI barrier occurs, with
progressive failure of mucosal immunity and leakage into the systemic circulation of
bacterial by-products, such as lipopolysaccharide (LPS) and bacterial DNA fragments which
contribute to immune activation even in patients with good virologic control (Brenchley
Nature Med 2006, Jiang JID 2009, Ferri JID 2010, Estes PLoS Pathog 2010). Microbial
translocation is defined as the transfer of gut derived microbes and/or microbial products to
systemic circulation without overt bacteremia. Different markers may be used in order to
evaluate this phenomenon: 16S DNA, LPS or its soluble receptor LBP (LPS Binding Protein),
sCD14 and I-FAB. These markers are not redundant because they describe different aspects of
microbial translocation. For instance 16S DNA measures global presence of microbes in plasma,
while LPS increase is mainly driven by gram negative bacteria.
Persistent immune activation has been implicated in risk of cardiovascular disease in HIV
infection and should receive as much attention as traditional CVD risk factors and ART
(Currier AIDS 2005, Friis-Moller NEJM 2003, Subramanian JAMA 2012, Shaked Arterioscler Thromb
Vasc Biol 2014, Kelesidis JID 2012). There are some reports associating LPS with subsequent
cardiovascular disease in HIV-infected patients (Pedersen 2013 Kelesidis JID 2012). Increased
levels of CD14s that persist in some treated HIV have been associated to an increased
all-cause mortality and HIV progression, as well as more rapid progression of carotid
atherosclerosis (Kelesidis T at al CROI 2012 Seattle). sCD163, a marker of monocyte and
macrophage activation, has been significantly correlated with aortic inflammation
(Subramanian S, JAMA 2012). Associations of one or more markers of microbial translocation
with characteristics of coronary injuries (stenosis, volume, mass and type of coronary
plaques) have not yet been studied.
