Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT06258122 |
Other study ID # |
CREPATS 17 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
March 15, 2024 |
Est. completion date |
March 15, 2025 |
Study information
Verified date |
February 2024 |
Source |
Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida |
Contact |
Yasmine DUDOIT |
Phone |
+33142164181 |
Email |
yasmine.dudoit[@]aphp.fr |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical Trial Summary
Main objective is:
- To characterize the evolution of the immuno-virological profile of circulating blood
cells and immune aging in patients who had participated to TEMPO-1 in 2007-2008
- To evaluate the role of immune aging and inflammatory profile in the occurrence of
comorbidities in HIV-infected individuals over a 15-year period
The alterations that affect the innate and adaptive immune cell compartments in HIV-infected
patients are reminiscent of the process of immune aging, characteristic of old age. These
alterations, the presumed cause of which is the chronic systemic immune activation
established in patients, contribute to the depletion of lymphoid resources which probably
leads to the decline of immune competence with the progression of HIV disease.
The comparison between HIV-1-infected patients and uninfected older adults goes beyond the
mere appearance of immunosenescence and extends to the deterioration of a number of
physiological functions linked to inflammation and to systemic aging.
By inducing persistent and lasting immune activation, HIV-1 infection is now considered a
model of accelerated immunosenescence and systemic aging. During this process, the immune
system quickly becomes exhausted, because the source of its exhaustion (i.e. HIV) cannot be
eliminated.
To determine which factors may contribute to immunosenescence in HIV-1 infection, we propose
an extensive immune and virological evaluation in patients who participated in a
cross-sectional assessment of immune functions and TEMPO-1 viral reservoirs after 15 years of
evolution in order to determine their immune and viral trajectories, to compare these
trajectories with the major clinical events and the comorbidities occurring in them.
Description:
Growing old with HIV has become a reality thanks to major advances in antiretroviral therapy.
Nearly 40 years after the discovery of the AIDS virus, there are more and more seniors living
with HIV. Currently, the median age of HIV-positive people in France is 49 years old. 50% of
HIV-positive people are over 50 years old (compared to 8.5% in 1993, 28% in 2010) and 16%
over 60 years old. As for discoveries of seropositivity, 20% are in people over 50 years old.
According to data from the Dutch ATHENA cohort, the proportion of HIV-infected people aged 50
and over is expected to increase to 73% in 2030.
Thus, if HIV infection has become a chronic disease, with lower mortality we observe a
consequent increase in age-related non-infectious comorbidities. Total healthy life
expectancy remains reduced among PLHIV compared to uninfected people of the same age, and
more than 50% of deaths are due to non-AIDS comorbidities. This polypathology occurs more
frequently and at a younger age than in the general population, and notably combines cancers,
risk factors and cardiovascular diseases, neurocognitive, bone diseases and chronic renal
insufficiency. In 2030, it is estimated that 84% of PLHIV will have at least one of these
comorbidities (vs. 29% in 2010), and that 28% will have at least 3, mainly cardiovascular.
Some of these comorbidities are linked to the long-term use of ARVs (reverse transcriptase
inhibitors, protease inhibitors, integrase inhibitors) leading in particular to metabolic
toxicities (dyslipidemia, insulin resistance), renal, bone, endothelial and mitochondrial.
However, these toxicities have decreased over time and with pharmacological progress.
n addition to individual or environmental factors such as smoking, a sedentary lifestyle, and
classic cardiovascular risk factors, HIV seems to contribute to an acceleration of aging.
The finding of an increased prevalence of non-HIV-related comorbidities such as
cardiovascular disease, cancer, renal failure, liver disease, osteopenia and osteoporosis, as
well as neurocognitive impairments is reminiscent of classic complications among elderly
people with a biological profile marked by inflammation.
Another point in common between PLHIV and the elderly is their prolonged exposure to
medications, often constituting polypharmacy.
Thus, antiretroviral molecules, taken by patients for decades for the majority of them, have
unfortunately been responsible for various toxicities. First generation ARVs caused cellular
disorders with mitochondrial damage for NRTIs such as zidovudine, didanosine or stavudine,
metabolic disorders with protease inhibitors. However, the most recent class of molecules,
INIs, is not free from toxicities. Indeed, several studies have shown abnormal weight gain
with a risk of diabetes and more recently hypertension.
The biological hallmarks of aging are now better understood and include stem cell exhaustion,
genomic instability, telomere attrition, impaired intercellular communication, epigenetic
alterations, loss of proteostasis, mitochondrial dysfunction and cellular senescence.
Immunologically, aging is associated with a decline in the competence of the immune system
called immunosenescence. It is characterized by several features that affect the adaptive and
innate immune compartment, as well as the hematopoietic compartment. It is also associated
with a high level of secretion of pro-inflammatory cytokines at baseline, called
"inflammation", leading to a decreased ability to mount an effective immune response to
antigens. We classically describe:
- A decrease in the number of naive T lymphocytes (LT), secondary to thymic involution
- An accumulation of memory cells and a restriction of the antigen receptor repertoire.
This is notably determined by the involution of the thymus and the persistence of
infectious agents such as cytomegalovirus,
- Shortening of telomeres
- Changes in the gene expression profile within T lymphocyte subpopulations affecting both
surface markers and chemokine/cytokine receptors, effector molecules or transcription
players.
- A low-grade chronic systemic inflammatory condition called "inflamm-aging". It is
characterized by the increased production of proinflammatory cytokines such as IL-1,
IL-6, "tumor necrosis factor alpha" (TNF-α) as well as the production of C-reactive
protein (CRP). The level of this proinflammatory state is associated with a worse
prognosis in elderly patients: increased morbidity and mortality, sarcopenia and
frailty.
These global immune changes observed with age contribute in particular to morbidity and
mortality linked to infections (in particular via a reduction in the vaccine response) and
cancers.
In 2007/2008, with the aim of describing and understanding the different viral and immune
phenomena in treated or untreated PLHIV, we carried out a cross-sectional observational study
on 240 patients carrying HIV-1.
The TEMPO study included a similar assessment of immune performance in an age- and
sex-matched control population. This TEMPO study allowed us to establish the following
conclusions:
- massive depletion of CD4+ T cells occurs during HIV-1 infection, such that maintenance
of adequate levels of CD4+ T cells depends primarily on the ability to replenish
depleted lymphocytes, i.e. - say lymphopoiesis.
- Marked deficiency of primary lymphoid immune resources is seen with failure to maintain
adequate lymphocyte numbers.
- Systemic immune activation has emerged as a major correlate of impaired lymphopoiesis,
which can be partially reversed by prolonged antiretroviral therapy.
Importantly, disease progression despite elite control of HIV replication or virologic
success on antiretroviral therapy has been associated with persistent damage to the
lymphopoietic system or exhaustion of lymphopoiesis.
These results highlight the importance of primary hematopoietic resources in HIV pathogenesis
and response to antiretroviral therapy.
TEMPO-2 is a cross-sectional study of PLHIV which will evaluate in depth the
immuno-virological status of 100 patients studied in the same way 15 years ago (TEMPO-1). The
complete history of clinical and biological events will be analyzed over their 15 years of
follow-up in the same hospital.
The study includes two groups: one comprising HIV-infected patients (100 PLHIV) and the
second comprising subjects not infected with HIV. Both groups participated in the initial
study (TEMPO-1) conducted 15 years ago, with an in-depth assessment of immune and virological
status.
The immune aging index of this HIV population will be compared to that of a control
population of non-HIV subjects who both participated in TEMPO-1 in 2007/2008.
We will focus on the dynamics of immune resources, particularly on hematopoietic progenitors.
This approach will allow us to follow the biological trajectory of relevant immune factors
and assess how these variables evolve over time between the two time points.