A 6-month interruption of antiretroviral therapy improves adipose tissue function in HIV-infected patients: the ANRS EP29 Lipostop Study.
ABSTRACT To examine the reversibility of adipose tissue alterations in HIV-infected patients after a 6-month interruption of antiretroviral therapy (ART).
Forty HIV-infected patients on stable effective ART were enrolled, 33 of them completed the study. Patients underwent a physical examination, laboratory tests and needle biopsy of subcutaneous abdominal adipose tissue both at inclusion and at month 6. Changes in fat morphology, mitochondrial DNA (mtDNA) content and gene expression were examined in 29, 23 and 20 patients, respectively.
Body fat distribution was not clearly modified at month 6. Adipose tissue inflammation improved markedly, with fewer infiltrating macrophages and fewer tumour necrosis factor alpha (TNFalpha)- and interleukin 6 (IL6)-expressing cells. Expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and of markers of mitochondrial function and biogenesis (cytochrome oxidase 2 and PPAR-gamma coreceptor 1alpha) improved after protease inhibitor (PI) withdrawal. In patients who stopped taking stavudine or zidovudine, the number of TNFalpha- and IL6-expressing cells was lower at month 6 than at month 0, and so was CD68 expression, a macrophage marker. Adipocyte mitochondrial status also improved, with lower mitochondrial density and cytochrome oxidase 4 mRNA levels, and higher mtDNA content. Sterol regulatory element binding protein 1 mRNA levels increased, reflecting better adipocyte differentiation.
A 6-month ART interruption markedly improved adipose tissue functions, although fat distribution did not visibly change. Stavudine and zidovudine were associated with marked inflammation, which improved when these drugs were withdrawn; they also had a negative effect on differentiation and mitochondrial status. PIs were also associated with altered adipocyte differentiation and mitochondrial status. These data clearly show the detrimental effect of antiretroviral drugs, in particular thymidine analogues, on adipose tissue and argue for switch strategies sparing these drugs.
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ABSTRACT: HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT.PLoS ONE 01/2014; 9(2):e89088. · 3.73 Impact Factor
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ABSTRACT: Background Few data report the prevalence in actual clinical settings of lipodystrophy (LD), and in particular of facial lipoatrophy (LA), in HIV infected patients treated with long-term antiretroviral therapy (ART). Methods French, multicenter, cross-sectional, observational study in HIV-infected patients on continuous antiretroviral therapy (ART) for more than 12 months. The main objective was to assess the prevalence of facial LA in this population. Additional objectives were to make the same assessments for non-facial LA and lipohypertrophy.The presence of LD signs, type, severity was assessed by clinicians and compared with patient self evaluation through two questionnaires. Results 2131 assessable patients had a median age of 46 years and a median time on ART of 10 years. Physicians diagnosed facial LA in 54% of patients and these subjects had received ART for a longer duration than those without LA. Thymidine analog usage was associated with an increased likelihood of facial LA, but 28% patients recently treatment-initiated (1-5 years) were also affected. At other sites, LA and lipohypertophy were respectively diagnosed in 59% and 57% cases. The concordance between physician and patient assessments was good for facial and buttocks LA. Conclusion In this study, facial LA affects more than half of subjects and is frequent even among the most recently treated patients. The prevalence of facial LA significantly increases with the duration of ART, with male gender, HCV co-infection and non-African origin being independent risk factors. Lipohyperthophy is frequent and appears early after ART initiation.AIDS research and human retroviruses 12/2012; · 2.18 Impact Factor
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ABSTRACT: Several alterations in nuclear envelope proteins building up the lamina meshwork beneath the inner nuclear membrane (mutations in lamins A/C, alterations of prelamin-A maturation, lamin B mutations or deregulation) have been shown to be responsible for or associated to human lipodystrophic syndromes. Lipodystrophic syndromes are rare and heterogeneous diseases, either genetic or acquired, characterized by generalized or partial fat atrophy associated with metabolic complications comprising insulin-resistant diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Recent advances in the molecular genetics of different types of lipodystrophies generally pointed to primary adipocyte alterations leading to impaired adipogenesis and/or deregulation of the adipocyte lipid droplet. However, the precise mechanisms linking nuclear envelope abnormalities to lipodystrophies remain largely unknown. The phenotype of nuclear envelope-linked lipodystrophies ranges from the typical Familial Partial Lipodystrophy of the Dunnigan type (FPLD2), due to heterozygous substitutions of the 482nd arginine of lamins A/C, to complex diseases that can combine lipodystrophy, metabolic complications, muscular or cardiac alterations and/or signs of accelerated aging. In this review we present the clinical, tissular and cellular characteristics of the nuclear envelope-linked lipodystrophies, as well as their hypothetical pathophysiological mechanisms.Seminars in Cell and Developmental Biology 01/2013; · 6.20 Impact Factor