Accelerated Aging, HIV Infection, Antiretroviral Therapies

HIV Infection Clinical Trial

— EP 45  

Official title:

Accelerated Aging, HIV Infection, Antiretroviral Therapies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01038999
• Other study ID #: 2008-A00905-50
• Status: Completed
• Phase: N/A
• First received: December 23, 2009
• Last updated: December 26, 2012
• Start date: April 2009
• Est. completion date: March 2012

Study information

• Verified date: December 2012
• Source: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Observational

Clinical Trial Summary

The main goal is to confirm, among HIV1-infected patients, data from in vitro studies showing that antiretroviral therapies induce an accelerated aging through the same mechanisms than genetic laminopathies or than "physiological " aging, that is through the synthesis and persistence of farnesylated prelamin A. The secondary goal is to measure the impact of HIV infection and of antiretroviral therapies on markers of cell ageing (proteasome, mitochondria, telomere). The perspective is to fix antiretroviral therapy side effects using the same drug combination that will be used in few weeks in Marseille to treat children suffering from progeria

Description:

Protease inhibitors block viral protease, as well as various other cell enzymes : ZMPSTE24 cliping off prelamin A into mature lamin A ; at least one of the Golgi proteases involved in the release of SREBP, controlling the transcription of lipid metabolism regulating genes ; mitochondrial proteases involved in the importation and further maturation of nuclear genome encoded proteins ; proteasome regulating the transcription of several genes through NF-B ; P450 cytochromes. Nucleosides inhibitors of the viral reverse transcriptase exhibit nuclear and mitochondrial DNA toxicity, disrupt lipid and protein glycosylation and inhibit telomerase. Therefore antiretroviral therapies target several pathways involved in accelerated or normal aging. Their combined effects are added to viral infection direct symptoms or to cell abnormalities induced by viral proteins.

Our multicentric (the 3 CISIH from Marseille, Nice and Montpellier) 3 year- long study will analyse 50 HIV1-infected naive patients (A group), apparied to 50 age- and sex-matched seronegative control subjects (recruited by CIC-UPCET of Marseille) and 100 HIV1-infected patients in first line of antiretroviral therapy for at least 12 months (B group). Patients of group A and B will be recruited in the 3 clinical unit. The HIV1- infected patients will be evaluated four times, at baseline, then every 12 months during 3 years. In case of initiation or changing of antiretroviral therapy, patients will be evaluated once more. Control subjects will be only evaluated at baseline.

Peripheral blood biological tests will be the following [Laboratory designation] : i/ viral load measurement, PBMC isolation, DNA extraction, proviral DNA measurement, cell and DNA storage [Virology, Timone CHU, Marseille]; ii/ assays of CD4, CD8, glycemia, insulinemia, HOMA, total-, LDL- and HDL-cholesterol, triglycerides [Biochemistry labs from the 3 CHU] ; iii/ antiretroviral drug assay (mass spectrometry) [Pharmacokinetics, Timone CHU, Marseille]; iv/ detection (western blotting, immunocytochemistry combined to image analysis of nuclear abnormalities) of PBMC nuclear, cytosolic and mitochondrial targets of antiretroviral drugs : A and B lamins, NF-B + I-B and proteasome activity assay, CD36 (glycosylation), mitochondrial Hsp70, ROS mitochondrial production, mitochondrial inner membrane potential, cytochrome C oxidase subunits 2 and 4 [Cell Biology, Timone CHU, Marseille] ; v/ genotyping the antiretroviral targets : lamin A (ZMPSTE24) and B (Rce1) processing proteases, Golgi SREBP-releasing proteases (MBTPS1 and S2), mitochondrial deoxynucleoside transporters (SLC25A4 to A6), mitochondrial proteases (MPPA, paraplegin) involved in processing of nuclear encoded proteins during their mitochondrial import ; quantitative PCR measurement of telomere length [Molecular Genetics, Timone CHU, Marseille]. Marseille's CIC-UPCET collaborated to the protocol design, will recruit control subjects and will be responsible for statistical treatment of data.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: March 2012
• Est. primary completion date: April 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

Age = 18 years and <65 years Able to give written consent Covered by French Social Security Non infected by HIV-2

• - A group HIV1-infected naive patients

• -B group infected patients in first line of antiretroviral therapy for at least 12 months

• -C group HIV seronegative Confirmed by a fast test of screening of the HIV at day one of study

Exclusion Criteria:

• Age < 18 years and > 65 years

• Not Able to give written consent

• Not Covered by French Social Security

• Infected by HIV-2

• treated by statin or biphosphonat amino

• concomitant treatment: diabetic or testosteron

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Aging Accelerated
• Antiretroviral Therapies
• HIV Infection
• HIV Infections
• Infection

Intervention

Biological:
• Peripheral blood biological tests
A group and B group will be evaluated three times, at baseline, then every 12 months during 3 years. In case of initiation or changing of antiretroviral therapy, patients will be evaluated once more. Control subjects will be only evaluated at baseline.

Locations

Country	Name	City	State
France	ANRS center from Marseille, Timone and Montpellier and Nice	country of French

Sponsors (1)

Lead Sponsor	Collaborator
French National Agency for Research on AIDS and Viral Hepatitis

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	lamin A measurement by western blotting			No
Secondary	Peripheral blood biological tests (cellular, molecular genetic)			No

External Links

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