Clinical trial NCT01038999: Accelerated Aging, HIV Infection, Antiretroviral Therapies
Official title: Accelerated Aging, HIV Infection, Antiretroviral Therapies
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV Infection
Aging Accelerated
Antiretroviral Therapies
Keywords: Complementary Therapies
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
First posted: 2009-12-24
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 50 HIV1-infected naive patients (A group), apparied to 50 age- and sex-matched seronegative control (C group) subjects and 100 HIV1-infected patients in first line of antiretroviral therapy for at least 12 months (B group)

Brief 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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: lamin A measurement by western blotting
Secondary outcomes:
measure: Peripheral blood biological tests (cellular, molecular genetic)
Other outcomes:
Locations:
city: country of French
country: France
facility: ANRS center from Marseille, Timone and Montpellier and Nice
Study officials:
affiliation: CHU Sainte Marguerite -Marseille
name: Isabelle POIZOT-MARTIN
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Sainte Marguerite -Marseille
name: Marie-Pierre DROGOUL
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Sainte Marguerite -Marseille
name: Olivia FAUCHER
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Sainte Marguerite -Marseille
name: Amélie MENARD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Timone
name: Joëlle MICALLEF-ROLL
role: PRINCIPAL_INVESTIGATOR
affiliation: CISIH CHRU Gui de Chauliac- Montpellier
name: Jacques REYNES
role: PRINCIPAL_INVESTIGATOR
affiliation: CISIH CHU Nice
name: Pierre DELLAMONICA
role: PRINCIPAL_INVESTIGATOR
affiliation: INSERM UMR S910 MARSEILLE
name: Pierre CAU
role: PRINCIPAL_INVESTIGATOR
affiliation: Laboratoire Virologie Marseille
name: Catherine TAMALET
role: PRINCIPAL_INVESTIGATOR
affiliation: Unité INSERM U911 Marseille
name: Bruno LACARELLE
role: PRINCIPAL_INVESTIGATOR
affiliation: Laboratoire Génétique Moléculaire Marseille
name: Nicolas LEVY
role: PRINCIPAL_INVESTIGATOR
affiliation: Laboratoire biologie cellulaire Marseille
name: Patrick ROLL
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.