To examine the reversibility of adipose tissue alterations in HIV-infected patients after a 6-month interruption of antiretroviral therapy (ART).
Methods
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.
Results
Body fat distribution was not clearly modified at month 6. Adipose tissue inflammation improved markedly, with fewer infiltrating macrophages and fewer tumour necrosis factor a (TNFα)- and interleukin 6 (IL6)-expressing cells. Expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and of markers of mitochondrial function and biogenesis (cytochrome oxidase 2 and PPAR-γ coreceptor 1α) improved after protease inhibitor (PI) withdrawal. In patients who stopped taking stavudine or zidovudine, the number of TNFα- 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.
Conclusions
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 Stavudine and zidovudine were associated with marked inflammation, which improved when these drugs were withdrawn; they also had a negative effect on differentiation and mitochondrial status.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.
References
1.
GrinspoonS., CarrA.Cardiovascular risk and body-fat abnormalities in HIV-infected adults.N Engl J Med2005; 352: 48–62.
2.
NolanD., MallalS.Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms.Antivir Ther2004; 9: 849–863.
3.
GougeonM.L., PenicaudL., FromentyB., LeclercqP., ViardJ.P., CapeauJ.Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations.Antivir Ther2004; 9: 161–177.
4.
VillaroyaF., DomingoP., GiraltM.Lipodystrophy associated with highly active antiretroviral therapy for HIV infection: the adipocyte as a target of antiretroviral-induced mitochondrial toxicity.Trends Pharmacol Sci2005; 26: 88–93.
5.
SavesM., CheneG., DucimetiereP.Risk Factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population.CID2003; 37: 292–297.
6.
NolanD., HammondE., JamesI.Contribution of nucleoside-analogue reverse trancriptase inhibitor therapy to lipoatrophy from the population to the cellular level.Antivir Ther2003; 8: 617–626.
7.
NoorM.A., LoJ.C., MulliganK.Metabolic effects of indinavir in healthy HIV-seronegative men.AIDS2001; 15: F11–18.
8.
NoorM.A., FlintO., MaaJ.F.Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically.AIDS2006; 20: 1813–1821.
9.
JemsekJ., ArathoonE., ArlottiM.Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients.CID2005; 42: 273–280.
10.
HaubrichR., RiddlerS., DiRienzoG.Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection.14th Conference on Retroviruses & Opportunistic Infections. 26–28 February 2007, Los Angeles, CA, USA. Oral Abstract 38.
11.
GallantJ.E., StaszewskiS., PozniakA.Efficacy and safety of tenofivir DF vs stavudine in combination therapy in antiretroviral-naive patients.JAMA2004; 292: 191–201.
12.
PodzamczerD., FerrerE., SanchezP.Less lipoathorphy and better lipid profile with abacavir as compared to stavudine.J Acquir Immune Defic Syndr2007; 44: 139–147.
13.
Ben-RomanoR., RudichA., EtzionS.Nelfinavir induces adipocyte insulin resistance through the induction of oxidative stress: differential protective effect of antioxidant agents.Antivir Ther2006; 11: 1051–1060.
14.
LagathuC., KimM., MaachiM.HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo.Biochimie2005; 87: 65–71.
15.
LagathuC., BastardJ.P., AuclairM.Antiretroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammatory cytokines and adiponectin in vitro.Antivir Ther2004; 9: 911–920.
16.
LagathuC., EustaceB., FrantzD.Some HIV-antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages.Antivir Ther2007; 12: 489–500.
17.
BoccaraF., CaronM., AuclairIrbesartan, an angiotensin II receptor I blocker, prevents the adverse efects of HIV antiretrovirals on adipocyte functions.Antivir Ther2006; 11: L7.
18.
CaronM., AuclairM., LagathuC.The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro.AIDS2004; 18: 2127–2136.
19.
El HadriK., GlorianM., MonsempesC.In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3t3 and human preadipocytes or adipocytes.J Biol Chem2004; 279: 15130–15141.
20.
BastardJ.P., CaronM., VidalH.Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance.Lancet2002; 359: 1026–1031.
21.
LloretaJ., DomingoP., PujolR.M.Ultrastructural features of highly active antiretroviral therapy-associated partial lipodystrophy.Virchows Arch2002; 441: 599–604.
22.
PaceC.S., MartinA.M., HammondE.L., MamotteC.D., NolanD.A., MallalS.A.Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients.Antivir Ther2003; 8: 323–331.
23.
JanV., CerveraP., MaachiM.Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients.Antivir Ther2004; 9: 555–564.
24.
McComseyG.A., PaulsenD.M., LonerganJ.T.Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine.AIDS2005; 19: 15–23.
25.
KannistoK., SutinenJ., KorsheninnikovaE.Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy.AIDS2003; 17: 1753–1762.
26.
MartinA., SmithD.E., CarrA.Mitochondrial Toxicity Study Group. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study.AIDS2004; 18: 1029–1036.
27.
MoyleG.J., SabinC.A., CartledgeJ.RAVE (Randomized Abacavir versus Viread Evaluation) Group UK. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy.AIDS2006; 20: 2043–2050.
28.
Strategies for the management of antiretroviral therapy (SMART) study group, El-SadrW.M., LundgrenJ.D., NeatonJ.D.CD4+ count-guided interruption of antiretroviral treatment: SMART study.N Engl J Med2006; 355: 2283–2296.
29.
LihnA.S., RichelsenB., PedersenS.B.Increased expression of TNF-α, IL-6, and IL-8 in HALS: implications for reduced adiponectin expression and plasma levels.Am J Physiol Endocrinol Metab2003; 285: E1072–1080.
30.
WeisbergS.P., McCannD., DesaiM., RosenbaumM., LeibelR.L.Obesity is associated with macrophage accumulation in adipose tissue.J Clin Invest2003; 112: 1796–1808.
31.
JonesS.P., QaziN., MoreleseJ.Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens.J Acquir Immune Defic Syndr2005; 40: 565–572.
32.
ChaparroJ., ReedsD.N., WenW.Alterations in thigh subcutaneous adipose tissue gene expression in protease inhibitor-based highly active antiretroviral therapy.Metabolism2005; 54: 561–567.
33.
MallonP.W., UnemoriP., SedwellR.In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA.J Infect Dis2005; 191: 1686–1696.
34.
NoorM.A., ParkerR.A., O'MaraE.The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults.AIDS2004; 18: 2137–2144.
35.
KimM.J., JardelC., BarthélémyC.Preserved cytochrome c oxidase activity despite mtDNA depletion in adipose tissue of HIV-infected patients with lipodystrophyAntivir Ther2005; 10Suppl 3: L8.
36.
CaronM., AuclairM., DonadilleB.Lipodystrophies linked to HIV protease inhibitor therapy and mutations in A type lamins are both associated with prelamin A accumulation and premature senescence.Antivir Ther2006; 11: L30.
