| |
The Canadian HIV and aging cohort study - determinants of increased risk of cardio-vascular diseases in HIV-infected individuals: rationale and study protocol
|
| |
| |
Download the PDF here
from Jules: its good that Canada is now beginning an HIV & Aging Cohort. Such cohorts have been ongoing for years in Western Europe & the USA. What we need most are programs that provide services NOW to aging patients & for better research into understanding the science of aging in HIV & potential interventions. There is no funding dedicated to special services for aging HIV+ in the USA. the RWCA & HRSA should carve out services for these patients & their clinics. It is shameful that this has not been done already, they are missing the boat. I advise & warn this will become a gigantic problem & will become an explosive problem, and it is essentially being ignored with cure & PrEP sucking the air out of the room. Aging should have equal footing with cure & PrEP in terms of funding & attention, this will come back to haunt advocates, researchers & the NIH & NAIAID who have not paid adequate attention to my issues mentioned above, and HRSA & RWCA advocates too.
"The consequence of chronic immune activation is the development of a senescent immune phenotype, with impaired thymic function, reduced T-cell repertoire and regeneration potential and T cell exhaustion, similarly to what is observed in aging [19, 20]."
BMC Infectious DiseasesBMC series - open, inclusive and trusted June 202017
Madeleine Durand1* , Carl Chartrand-Lefebvre2, Jean-Guy Baril3, Sylvie Trottier3, Benoit Trottier3, Marianne Harris4, Sharon Walmsley5, Brian Conway5, Alexander Wong6, Jean-Pierre Routy7, Colin Kovacs8, Paul A. MacPherson9,
Kenneth Marc Monteith9, Samer Mansour9, George Thanassoulis10, Michal Abrahamowicz11, Zhitong Zhu11, Christos Tsoukas12, Petronela Ancuta13, Nicole Bernard14, Cécile L. Tremblay13 and For the investigators of the
Canadian HIV and Aging Cohort Study
Abstract
Background
With potent antiretroviral drugs, HIV infection is becoming a chronic disease. Emergence of comorbidities, particularly cardiovascular disease (CVD) has become a leading concern for patients living with the infection. We hypothesized that the chronic and persistent inflammation and immune activation associated with HIV disease leads to accelerated aging, characterized by CVD. This will translate into higher incidence rates of CVD in HIV infected participants, when compared to HIV negative participants, after adjustment for traditional CVD risk factors. When characterized further using cardiovascular imaging, biomarkers, immunological and genetic profiles, CVD associated with HIV will show different characteristics compared to CVD in HIV-negative individuals.
Methods/design
The Canadian HIV and Aging cohort is a prospective, controlled cohort study funded by the Canadian Institutes of Health Research. It will recruit patients living with HIV who are aged 40years or older or have lived with HIV for 15years or more. A control population, frequency matched for age, sex, and smoking status, will be recruited from the general population. Patients will attend study visits at baseline, year 1, 2, 5 and 8. At each study visit, data on complete medical and pharmaceutical history will be captured, along with anthropometric measures, a complete physical examination, routine blood tests and electrocardiogram. Consenting participants will also contribute blood samples to a research biobank. The primary outcome is incidence of a composite of: myocardial infarction, coronary revascularization, stroke, hospitalization for angina or congestive heart failure, revascularization or amputation for peripheral artery disease, or cardiovascular death.
Preplanned secondary outcomes are all-cause mortality, incidence of the metabolic syndrome, incidence of type 2 diabetes, incidence of renal failure, incidence of abnormal bone mineral density and body fat distribution.
Patients participating to the cohort will be eligible to be enrolled in four pre-planned sub-studies of cardiovascular imaging, glucose metabolism, immunological and genetic risk profile.
Discussion
The Canadian HIV and Aging Cohort will provide insights on pathophysiological pathways leading to premature CVD for patients living with HIV.
Background
As a result of recent advances in antiretroviral therapy (ART), HIV-infected individuals live longer, with an estimated life expectancy that ranges from 20 to 50years following infection, and in some cases could reach normal life expectancy [1, 2, 3]. Factors that impact on longevity include: the age at infection, the nadir CD4 cell count, the time spent with CD4 counts >500 cells/mm3, and other variables [1, 3, 4, 5, 6, 7, 8]. In 2015, it was estimated that 50% of HIV-infected persons were >50years of age, making them susceptible to diseases related to aging [2, 3, 9]. Furthermore, some age-related diseases may be overrepresented in the HIV population, and appear approximately 5 to 10years earlier than in the general population [10, 11, 12]. This has led to the concept of “premature aging” in HIV-infected individuals [13, 14]. This term is controversial, since not all HIV-infected individuals show signs of accelerated aging, and not all components of the aging phenotype have been observed prematurely in the HIV-population. Co-morbid conditions of particular concern include cardiovascular diseases (CVD), the metabolic syndrome (MetS), early onset of osteoporosis, and renal impairment. The pathophysiological processes leading to these phenotypes are complex and not completely understood.
Several hypotheses have been put forward to try to explain premature aging: mitochondrial toxicity, immunodeficiency, antiretroviral toxicity, lifestyle, and a chronic state of immune activation [15, 16, 17, 18]. The consequence of chronic immune activation is the development of a senescent immune phenotype, with impaired thymic function, reduced T-cell repertoire and regeneration potential and T cell exhaustion, similarly to what is observed in aging [19, 20].
Large cohort studies have shown an increased risk of CVD in HIV-infected individuals. Compared to age and sex matched controls, we found a hazard ratio for myocardial infarction associated with HIV infection of 2.13 (95% confidence interval [CI] 1.69-2.63) in local data from a Québec administrative database [21]. In the international Data Collection on Adverse Events of anti-HIV Drugs (D:A:D) cohort including 33,347 HIV positive patients, an overall rate of myocardial infarction of 3.48/1000 person-years was reported [22, 23]. A meta-analysis of observational and randomized controlled trials reporting CVD showed that the relative risk of CVD was 1.61 (95% CI 1.43-1.81) among ART-naïve HIV-infected compared with HIV-uninfected people [24, 25].
The overrepresentation of traditional cardiovascular risk factors, particularly smoking, in HIV-infection population can explain part of the excess CVD risk [26]. However, traditional risk factors may not explain the totality of the excess risk. We wish to further characterize the causative pathways and identify predictors of this premature CVD associated with HIV infection. Through better understanding of the particular physiopathology underlying CVD in HIV, our ultimate aim is to prevent negative outcomes and optimize primary care interventions. This study will focus on identifying the type, frequency and determinants of premature CVD in HIV-infected individuals.
Study hypothesis
The chronic and persistent inflammation associated with HIV disease leads to accelerated aging, characterized by premature CVD, altered metabolism and immune senescence. This will translate into higher incidence rates of CVD in HIV infected participants, when compared to HIV negative participants, after adjustment for traditional CVD risk factors. When characterized further using cardiovascular imaging, biomarkers, immunological and genetic profiles, CVD associated to HIV will show different characteristics compared to CVD in HIV-uninfected individuals.
Discussion
The Canadian HIV and Aging Cohort Study is a large, controlled, prospective cohort. It aims to recruit 1000 participants living with HIV, and 1000 participants unexposed to HIV. While its primary endpoints are significant clinical events for patients living with HIV, the pre-planned sub-studies will increase our basic understanding of the complex interplay between the immune alterations caused by chronic HIV infection and CVD. The cohort will provide a strong base for future studies of comorbidities associated with aging with HIV.
Several methodological aspects of this cohort warrant further discussion. First, the age at enrolment of the participants living with HIV was carefully considered. As our main focus was cardiovascular health, recruiting participants who were too young would have led to low event rates and low power. Yet recruiting patients with HIV infection that is long-lasting might result in missing the early alterations of the cardiovascular system that are driven by the chronic state of inflammation found in those patients. We settled for an enrolment age of 40years or older, but planned that patients with very long-lasting HIV infection (15years or more) could be recruited even if younger than 40.
Selection of the HIV uninfected patients was another key aspect of our design. One strategy would have been to simply recruit patients from the general population through publicity campaigns, with a frequency matching for age and sex only. However, very large differences in traditional cardiovascular risk factors, particularly smoking, may have obscured the risk due to HIV, so we decided to frequency match the selection on smoking status as well. Also, as HIV infection is associated with certain lifestyles, which in turn could impact on the outcomes of our study, we elected to recruit our HIV uninfected cohort as well from clinics that treated our patients living with HIV. Those choices imply that our results will not be generalizable to the general population, but we felt that they suited our general aim to isolate the effect of HIV infection as much as possible.
Power calculations were based on event rates from the Framingham cohort [29]. These rates may not apply to the Canadian population, and may be lower now that aggressive treatment of cardiovascular risk factors is widespread. As such, we may lack power to detect differences in the occurrence of the primary endpoint. However, our power calculations were conservative, aiming to be able to detect HRs for our composite endpoint of 1.72 to 1.90, which is lower than the 2.13 95%CI [1.69-2.63] we observed in our own population [59].
Our study encompasses the entire research spectrum, from collection and analysis of epidemiological data on lifestyle, quality of life and medical co-morbidities to advanced fundamental imaging and immunological research. We have access to detailed epidemiological data, and a biobank with stored cells and plasma. Our team of experts also spans the whole research continuum from clinical to basic science, including community members, health practitioners, specialists in cardiology, immunology, virology, genetics, radiology, and internal medicine, with a balance between clinical and basic scientists. This study structure will allow rapid and in-depth investigations into novel immuno-metabolic pathways that lead to CVD in the setting of HIV infection.
Another important advantage of our cohort setting is the universal health care system that is available to all participants of our study. This will greatly contribute to alleviate discrepancies in healthcare that would be due to socioeconomic status. Central data collection and management is another strength. Overall, flexibility of the study structure, with possible addition of further sub-studies to the main cohort, is a major capacity-building aspect of this cohort.
We believe the Canadian HIV and Aging Cohort Study will be a powerful research tool to offer rapid responses to emerging clinical questions for people living with HIV and their healthcare providers.
Pre-planned sub-studies
Sub study 1 - characterization of atherosclerotic plaque
Lo reported increased prevalence of subclinical coronary atherosclerotic disease in HIV [43]. It is yet unclear if the composition of the atherosclerotic plaque in HIV is similar to that seen in the general population [36, 43, 44, 45]. More data are needed to characterize the atherosclerotic process, with possible implications for screening and treatment. In this sub-sub-study, 5 cardiac imaging modalities will be applied to characterize the atherosclerosis in HIV positive patients and compare it to that in HIV-negative controls: 1) positron emitting tomography (PET) scan of the ascending aorta and carotid arteries 2)carotid arteries ultrasound with measurement of intima-media thickness 3) cardiac computed tomography scan without injection of contrast media, 4) cardiac computed tomography scan with injection of contrast media, and 5) intravascular coronary ultrasound (in patients for whom coronary angiogram is clinically indicated). Most imaging modalities will be cross-sectional, but cardiac computed tomography scan and carotid arteries ultrasound will be repeated to assess progression of coronary artery disease.
Hypothesis
Atherosclerotic plaque has a different composition in HIV infected individuals, which can be described by imaging modalities.
Outcomes
For each of the imaging modalities, the primary outcome is difference in atherosclerotic plaque presence and composition between HIV+ and HIV-. For repeated measures (cardiac scan with contrast media), the outcomes include rate of progression of total plaque volume.
Sub-study 2-characterization of dysglycemia
There are conflicting results in the literature regarding relative prevalence and determinants of dysglycemia (defined as impaired fasting glucose, impaired glucose tolerance or diabetes) in HIV-infected patients compared to the HIV-negative population [46, 47, 48, 49]. Antiretrovirals, lipodystrophy, and altered metabolism due to long-lasting inflammation could contribute to development of dysglycemia in this population [49, 50]. In this sub-study, oral glucose tolerance tests will be used to assess patients at risk of or with known dysglycemia in a prospective fashion, with levels of biomarkers to further characterize the nature of HIV-associated dysglycemia.
Hypothesis
Dysglycemia in HIV infection is associated with a different metabolic profile. Precisely, we hypothesize there will be more endothelial dysfunction (as measured by increased ICAM1, VCAM1, and E-selectin), more coagulation activation (as measured by increased PAI-1 and fibrinogen), more oxidative stress (as measured by oxidized-LDL), and more inflammation (as measured by IL-6, TNF-α, CRP) in HIV+ than in HIV- patients with dysglycemia.
Outcomes
The primary outcome is difference in area under the curve for the biomarkers throughout the oral glucose tolerance test between HIV+ and HIV- patients.
Sub-study 3-characterization of immune profile in CVD
Globally impaired immunity secondary to HIV infection might contribute to the risk of CVD in HIV infected individuals via several pathways. Of particular interest is the depletion of Th17 lymphocytes, leading to microbial translocation from the gut, sustained immune activation, and eventually immune senescence [51, 52, 53, 54, 55]. In this sub-study, we will perform cross sectional immunological studies to better characterize the contribution of various immune profiles on development of CVD, and how those differ between HIV+ and HIV- individuals.
Hypothesis
CVD associated with HIV is immunologically distinct from CVD in HIV uninfected patients: impaired immunity induced by HIV infection leads to an immune risk profile that contributes to development of premature CVD.
Outcomes
Immunological analyses will focus on Th17 paucity, monocyte activation, Cytomegalovirus infection, and presence of an immune risk phenotype characterised by T-cell senescence and immune activation. The primary outcomes are specific to each of those three aspects. They involve measures of correlations between immune profiles and total coronary plaque volume, in participants with and without HIV.
Population and setting
For this sub study, the presence of CVD will be measured as total coronary plaque volume, which is measured on injected cardiac Computed tomography (CT) scan. Banked samples from all patients who undergo injected cardiac CT scan will be analyzed. The planned sample size is 190 patients in total.
Sub-study 4 - characterization of genetic profile in CVD
Several studies have reported that a genetic risk score is associated with incident and prevalent CVD [56, 57, 58]. It remains unknown whether a genetic predisposition for atherosclerosis could also potentiate HIV-specific mechanisms for CVD. We propose to evaluate whether a genetic risk score comprised of 30 single nucleotide polymorphisms (already validated in genome-wide association studies) can predict the presence of CVD, and whether the risk score is more strongly associated with CVD in HIV+ as compared to HIV- individuals.
Hypothesis
A genetic risk score will be more strongly associated with subclinical CVD in HIV+ than in HIV- participants.
Outcomes
The primary outcome is the difference in risk scores between HIV+ and HIV- patients with CVD.
|
|
| |
| |
|
|
|
