Ignite Creation Date:
2024-05-06 @ 8:07 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06258122
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-14
First Post:
2024-02-06
Brief Title:
Evolution of the Clinical Immuno-virological and Aging Trajectory of Patients Living With HIV
Sponsor:
Centre de Recherches et dEtude sur la Pathologie Tropicale et le Sida
Organization:
Centre de Recherches et dEtude sur la Pathologie Tropicale et le Sida
Study Overview
Official Title:
Evolution Over 15 Years 2008-2023 of the Clinical Immuno-virological and Aging Trajectory of Patients Living With HIV
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TEMPO2
Brief 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 ie 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
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 ie 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
Detailed 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 85 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 chemokinecytokine 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 20072008 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 ie - 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 20072008
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
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 chemokinecytokine 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 20072008 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 ie - 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 20072008
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None