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Accelerated Aging, HIV Infection, Antiretroviral Therapies

NCT ID: NCT01038999

Last Updated: 2012-12-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

200 participants

Study Classification

OBSERVATIONAL

Study Start Date

2009-04-30

Study Completion Date

2012-03-31

Brief Summary

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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

Detailed Description

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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.

Conditions

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HIV Infection Aging Accelerated Antiretroviral Therapies

Keywords

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Complementary Therapies

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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A HIV1-infected naive patients

Peripheral blood biological tests

Intervention Type BIOLOGICAL

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.

B HIV1-infected patients

in 1st line of ARV therapy for at least 12 months

Peripheral blood biological tests

Intervention Type BIOLOGICAL

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.

C= control Non infected HIV volunters

Peripheral blood biological tests

Intervention Type BIOLOGICAL

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.

Interventions

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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.

Intervention Type BIOLOGICAL

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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French National Agency for Research on AIDS and Viral Hepatitis

OTHER_GOV

Sponsor Role lead

Responsible Party

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French National Agency for Research on AIDS and Viral Hepatitis

Principal Investigators

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Isabelle POIZOT-MARTIN

Role: PRINCIPAL_INVESTIGATOR

CHU Sainte Marguerite -Marseille

Marie-Pierre DROGOUL

Role: PRINCIPAL_INVESTIGATOR

CHU Sainte Marguerite -Marseille

Olivia FAUCHER

Role: PRINCIPAL_INVESTIGATOR

CHU Sainte Marguerite -Marseille

Amélie MENARD

Role: PRINCIPAL_INVESTIGATOR

CHU Sainte Marguerite -Marseille

Joëlle MICALLEF-ROLL

Role: PRINCIPAL_INVESTIGATOR

CHU Timone

Jacques REYNES

Role: PRINCIPAL_INVESTIGATOR

CISIH CHRU Gui de Chauliac- Montpellier

Pierre DELLAMONICA

Role: PRINCIPAL_INVESTIGATOR

CISIH CHU Nice

Pierre CAU

Role: PRINCIPAL_INVESTIGATOR

INSERM UMR S910 MARSEILLE

Catherine TAMALET

Role: PRINCIPAL_INVESTIGATOR

Laboratoire Virologie Marseille

Bruno LACARELLE

Role: PRINCIPAL_INVESTIGATOR

Unité INSERM U911 Marseille

Nicolas LEVY

Role: PRINCIPAL_INVESTIGATOR

Laboratoire Génétique Moléculaire Marseille

Patrick ROLL

Role: PRINCIPAL_INVESTIGATOR

Laboratoire biologie cellulaire Marseille

Locations

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ANRS center from Marseille, Timone and Montpellier and Nice

Country of French, , France

Site Status

Countries

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France

References

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Perrin S, Cremer J, Faucher O, Reynes J, Dellamonica P, Micallef J, Solas C, Lacarelle B, Stretti C, Kaspi E, Robaglia-Schlupp A, Nicolino-Brunet C, Tamalet C, Levy N, Poizot-Martin I, Cau P, Roll P. HIV protease inhibitors do not cause the accumulation of prelamin A in PBMCs from patients receiving first line therapy: the ANRS EP45 "aging" study. PLoS One. 2012;7(12):e53035. doi: 10.1371/journal.pone.0053035. Epub 2012 Dec 28.

Reference Type DERIVED
PMID: 23285253 (View on PubMed)

Perrin S, Cremer J, Roll P, Faucher O, Menard A, Reynes J, Dellamonica P, Naqvi A, Micallef J, Jouve E, Tamalet C, Solas C, Pissier C, Arnoux I, Nicolino-Brunet C, Espinosa L, Levy N, Kaspi E, Robaglia-Schlupp A, Poizot-Martin I, Cau P. HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study. PLoS One. 2012;7(7):e41129. doi: 10.1371/journal.pone.0041129. Epub 2012 Jul 19.

Reference Type DERIVED
PMID: 22829920 (View on PubMed)

Related Links

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http://anrs.fr

Related Info

Other Identifiers

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2008-A00905-50

Identifier Type: -

Identifier Source: org_study_id