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A six-months ART interruption in HIV-infected patients improves adipose tissue morphology and gene expression (ANRS EP29 Lipostop)
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Reported by Jules Levin
8th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
San Francisco, Sept 24-26, 2006-09-27
Jacqueline Capeau reported this at the meeting.
M Kim, P Leclercq, P Cervera, E Lanoy, M Maachi, E Dorofeev, L Slama, MA Valentin, D Costagliola, A Lombes, JP Bastard, J Capeau
INSERM U680, U720, Université Pierre et Marie Curie
Paris, France
Background
Adipose tissue biopsies from patients with ART-related lipodystrophy present markedly altered morphology as compared to non-HIV infected controls.
Domingo AIDS 1999, Bastard and Caron Lancet 2002, Nolan AIDS 2003,
Jan and Cervera Antiviral Therapy 2004, Nolan Antiviral Therapy 2004
Results
A 6-months treatment interruption improved adipose tissue markers:
-- decreased inflammation: decreased macrophages, adipocytes and inflammatory cells positive for IL6 and TNFa
-- increased expression of adipogenic markers
-- improved mitochondrial markers
In patients stopping PI:
-- improved expression of the adipogenic marker PPARg
-- improved markers of mitochondrial biogenesis : PGC1-a and COX2
In patients stopping thymidine analogues :
-- decreased number of macrophages, lipogranulomas, adipocytes and inflammatory cells positive for IL6 and TNFa
-- improved expression of the adipogenic marker SREBP-1
-- improved mitochondrial markers mtDNA, COX4 and COX2/COX4 ratio
Author Conclusion:
-- PI are involved in altered adipose tissue differentiation and mitochondrial function
-- Thymidine analogues, stavudine and zidovudine, are involved in adipose tissue inflammation, mitochondrial and differentiation alterations
-- Other NRTIs probably also play a role in inflammation
-- PI and thymidine analogues act on adipose tissue at different levels
-- A 6-months treatment interruption allows a partial recovery of the adipose tissue alterations even if no differences were observed at the clinical level
-- Switch strategies are justified
Aim of Study and Protocol
Aim
- To evaluate, in HIV-related lipodystrophy, the factors linked to ART
- To evaluate the respective role of PI and thymidine analogues
- To analyse the reversibility of adipose tissue alterations
Adipose tissue morphology and the expression of adipose and mitochondrial markers were evaluated before and after a 6-months ART interruption
Protocol
- 40 well-controlled HIV-infected patients were included
- ART interruption for 6 months
- Clinical and biological evaluation at M0 and M6
- Virological evaluation every 2 months
- Abdominal subcutaneous fat biopsy at M0 and M6
- 33 patients completed the study
Pathology was performed in 29
mRNA analyses were performed in 20 (enough adipose tissue)
Patients' Description and Treatment
Age: median 41.7 years (27.5-66.8)
Sex: 80% male
Time since diagnosis: median 9.7 years (1.3-19.3)
33 patients until M6
-- 20 (61%) patients under NRTI without PI
-- 13 (39%) patients under NRTI + PI
2: ATZ, 4: ATZ/r, 3: NFV, 1: NFV/r, 1: IDV/r, 1 SQV/r 1: LPV/r
-- 21 (64%) patients under thymidine analogue
13 patients AZT
8 patients D4T
20 patients with mRNA analyses from fat biopsies
-- 12 patients without PI and 8 patients under NRTI + PI
-- 9 (45%) patients under thymidine analogue
8 patients AZT
1 patient D4T
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