Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity

References

• Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338: 853–60
   PubMed Web of Science ®Google Scholar
• Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12: F51–8
   PubMed Web of Science ®Google Scholar
• Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000; 14: F25–32
   PubMed Web of Science ®Google Scholar
• Friis-Møller N, Sabin CA, Weber R, d'Arminio MA, El Sadr WM, Reiss P, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349: 1993–2003
   PubMed Web of Science ®Google Scholar
• Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356: 1723–35
   PubMed Web of Science ®Google Scholar
• Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12: 1735–44
   PubMed Web of Science ®Google Scholar
• Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999; 354: 1112–5
   PubMed Web of Science ®Google Scholar
• Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1: 417–22
   PubMed Web of Science ®Google Scholar
• Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991; 337: 508–10
   PubMed Web of Science ®Google Scholar
• Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990; 322: 1098–105
   PubMed Web of Science ®Google Scholar
• Bissuel F, Bruneel F, Habersetzer F, Chassard D, Cotte L, Chevallier M, et al. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med 1994; 235: 367–71
   PubMed Web of Science ®Google Scholar
• Dalakas MC, Semino-Mora C, Leon-Monzon M. Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2′,3′-dideoxycytidine (ddC). Lab Invest 2001; 81: 1537–44
   PubMed Web of Science ®Google Scholar
• Fleischman A, Johnsen S, Systrom DM, Hrovat M, Farrar CT, Frontera WR, et al. Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab 2007; 292: E1666–73
   PubMed Web of Science ®Google Scholar
• Lo JC, Kazemi MR, Hsue PY, Martin JN, Deeks SG, Schambelan M, et al. The relationship between nucleoside analogue treatment duration, insulin resistance, and fasting arterialized lactate level in patients with HIV infection. Clin Infect Dis 2005; 41: 1335–40
   PubMed Web of Science ®Google Scholar
• Olano JP, Borucki MJ, Wen JW, Haque AK. Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was receiving zidovudine. Clin Infect Dis 1995; 21: 973–6
   PubMed Web of Science ®Google Scholar
• Larsson NG, Oldfors A. Mitochondrial myopathies. Acta Physiol Scand 2001; 171: 385–93
   PubMedGoogle Scholar
• Graziewicz MA, Longley MJ, Copeland WC. DNA polymerase gamma in mitochondrial DNA replication and repair. Chem Rev 2006; 106: 383–405
   PubMed Web of Science ®Google Scholar
• Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22: 685–708
   PubMed Web of Science ®Google Scholar
• Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87: 99–163
   PubMed Web of Science ®Google Scholar
• Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 2007; 8: 405–13
   PubMed Web of Science ®Google Scholar
• Wallace DC. Mitochondrial diseases in man and mouse. Science 1999; 283: 1482–8
   PubMed Web of Science ®Google Scholar
• Shuster RC, Rubenstein AJ, Wallace DC. Mitochondrial DNA in anucleate human blood cells. Biochem Biophys Res Commun 1988; 155: 1360–5
   PubMed Web of Science ®Google Scholar
• Wiesner RJ, Ruegg JC, Morano I. Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues. Biochem Biophys Res Commun 1992; 183: 553–9
   PubMed Web of Science ®Google Scholar
• Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2001; 2: 342–52
   PubMed Web of Science ®Google Scholar
• Shapiro TA, Englund PT. The structure and replication of kinetoplast DNA. Annu Rev Microbiol 1995; 49: 117–43
   PubMed Web of Science ®Google Scholar
• Falkenberg M, Larsson NG, Gustafsson CM. DNA replication and transcription in mammalian mitochondria. Annu Rev Biochem 2007; 76: 679–99
   PubMed Web of Science ®Google Scholar
• Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Disc 2003; 2: 812–22
   PubMed Web of Science ®Google Scholar
• Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002; 46: 716–23
   PubMed Web of Science ®Google Scholar
• Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS, et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001; 276: 40847–57
   PubMed Web of Science ®Google Scholar
• Martin JL, Brown CE, Matthews-Davis N, Reardon JE. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994; 38: 2743–9
   PubMed Web of Science ®Google Scholar
• Moyle G. Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism?. Drug Saf 2000; 23: 467–81
   PubMed Web of Science ®Google Scholar
• Lim SE, Copeland WC. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem 2001; 276: 23616–23
   PubMed Web of Science ®Google Scholar
• Pan-Zhou XR, Cui L, Zhou XJ, Sommadossi JP, Darley-Usmar VM. Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells. Antimicrob Agents Chemother 2000; 44: 496–503
   PubMed Web of Science ®Google Scholar
• Barile M, Valenti D, Passarella S, Quagliariello E. 3′-Azido-3′-deoxythmidine uptake into isolated rat liver mitochondria and impairment of ADP/ATP translocator. Biochem Pharmacol 1997; 53: 913–20
   PubMed Web of Science ®Google Scholar
• Barile M, Valenti D, Quagliariello E, Passarella S. Mitochondria as cell targets of AZT (zidovudine). Gen Pharmacol 1998; 31: 531–8
   PubMedGoogle Scholar
• Yamaguchi T, Katoh I, Kurata S. Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization. Eur J Biochem 2002; 269: 2782–8
   PubMedGoogle Scholar
• Anderson PL, Kakuda TN, Lichtenstein KA. The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis 2004; 38: 743–53
   PubMed Web of Science ®Google Scholar
• Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 2003; 17: 2159–68
   PubMed Web of Science ®Google Scholar
• Martin AM, Hammond E, Nolan D, Pace C, Den B, Taylor L, et al. Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. Am J Human Genetics 2003; 72: 549–60
   PubMed Web of Science ®Google Scholar
• Maagaard A, Holberg-Petersen M, Kollberg G, Oldfors A, Sandvik L, Bruun JN. Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients. Antivir Ther 2006; 11: 601–8
   PubMed Web of Science ®Google Scholar
• McComsey G, Tan DJ, Lederman M, Wilson E, Wong LJ. Analysis of the mitochondrial DNA genome in the peripheral blood leukocytes of HIV-infected patients with or without lipoatrophy. AIDS 2002; 16: 513–8
   PubMed Web of Science ®Google Scholar
• Walker UA, Bickel M, Lutke Volksbeck SI, Ketelsen UP, Schofer H, Setzer B, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002; 29: 117–21
   PubMed Web of Science ®Google Scholar
• Cherry CL, Nolan D, James IR, McKinnon EJ, Mallal SA, Gahan ME, et al. Tissue-specific associations between mitochondrial DNA levels and current treatment status in HIV-infected individuals. J Acquir Immune Defic Syndr 2006; 42: 435–40
   PubMed Web of Science ®Google Scholar
• Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS 2001; 15: 795–7
   PubMed Web of Science ®Google Scholar
• Côté HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002; 346: 811–20
   PubMed Web of Science ®Google Scholar
• Miró O, López S, Martinez E, Rodriguez-Santiago B, Blanco JL, Milinkovic A, et al. Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy. AIDS Res Hum Retroviruses 2003; 19: 1027–32
   PubMed Web of Science ®Google Scholar
• Imhof, A, Ledergerber, B, Gunthard, HF, Haupts, S, Weber, R, and the Swiss HIV Cohort Study. Risk factors for and outcome of hyperlactatemia in HIV-infected persons: is there a need for routine lactate monitoring?. Clin Infect Dis 2005;41:721–8.
   PubMed Web of Science ®Google Scholar
• Bolhaar MG, Karstaedt AS. A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receiving highly active antiretroviral therapy in Soweto, South Africa. Clin Infect Dis 2007; 45: 254–60
   PubMed Web of Science ®Google Scholar
• Sánchez-Conde M, de Mendoza C, Jimenez-Nacher I, Barreiro P, Gonzalez-Lahoz J, Soriano V. Reductions in stavudine dose might ameliorate mitochondrial-associated complications without compromising antiviral activity. HIV Clin Trials 2005; 6: 197–202
   PubMed Web of Science ®Google Scholar
• McComsey GA, Lo RV III, O'Riordan M, Walker UA, Lebrecht D, Baron E, et al. Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study. Clin Infect Dis 2008; 46: 1290–6
   PubMed Web of Science ®Google Scholar
• Bonnet F, Bonarek M, Morlat P, Mercie P, Dupon M, Gemain MC, et al. Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: a case–control study. Clin Infect Dis 2003; 36: 1324–8
   PubMed Web of Science ®Google Scholar
• Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004; 38: e79–80
   PubMed Web of Science ®Google Scholar
• Butt AA. Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. AIDS Read 2003; 13: 344–8
   PubMedGoogle Scholar
• de Mendoza C, Soriano V. The role of hepatitis C virus (HCV) in mitochondrial DNA damage in HIV/HCV-coinfected individuals. Antivir Ther 2005; 10(Suppl 2)M109–15
   PubMed Web of Science ®Google Scholar
• Moyle GJ, Datta D, Mandalia S, Morlese J, Asboe D, Gazzard BG. Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS 2002; 16: 1341–9
   PubMed Web of Science ®Google Scholar
• Boubaker K, Flepp M, Sudre P, Furrer H, Haensel A, Hirschel B, et al. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis 2001; 33: 1931–7
   PubMed Web of Science ®Google Scholar
• Gérard Y, Maulin L, Yazdanpanah Y, De La Tribonnière X, Amiel C, Maurage CA, et al. Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. AIDS 2000; 14: 2723–30
   PubMed Web of Science ®Google Scholar
• John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS 2001; 15: 717–23
   PubMed Web of Science ®Google Scholar
• Lonergan JT, Behling C, Pfander H, Hassanein TI, Mathews WC. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis 2000; 31: 162–6
   PubMed Web of Science ®Google Scholar
• Wohl DA, Pilcher CD, Evans S, Revuelta M, McComsey G, Yang Y, et al. Absence of sustained hyperlactatemia in HIV-infected patients with risk factors for mitochondrial toxicity. J Acquir Immune Defic Syndr 2001; 35: 274–8
   Google Scholar
• Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356: 1423–30
   PubMed Web of Science ®Google Scholar
• Lichtenstein KA. Redefining lipodystrophy syndrome: risks and impact on clinical decision making. J Acquir Immune Defic Syndr 2005; 39: 395–400
   PubMed Web of Science ®Google Scholar
• Buffet M, Schwazinger MA, Gourlain K, Bui P, Prevot M, Deleuze J, et al. Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy. J Clin Virol 2005; 33: 60–4
   PubMed Web of Science ®Google Scholar
• Cherry CL, Gahan ME, McArthur JC, Lewin SR, Hoy JF, Wesselingh SL. Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat. J Acquir Immune Defic Syndr 2002; 30: 271–7
   PubMed Web of Science ®Google Scholar
• Jones SP, Qazi N, Morelese J, Lebrecht D, Sutinen J, Yki-Jarvinen H, et al. Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens. J Acquir Immune Defic Syndr 2005; 40: 565–72
   PubMed Web of Science ®Google Scholar
• Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000; 14: 1309–16
   PubMed Web of Science ®Google Scholar
• McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion 2004; 4: 111–8
   PubMed Web of Science ®Google Scholar
• Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E, et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003; 17: 1329–38
   PubMed Web of Science ®Google Scholar
• Shikuma CM, Hu N, Milne C, Yost F, Waslien C, Shimizu S, et al. Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy. AIDS 2001; 15: 1801–9
   PubMed Web of Science ®Google Scholar
• McComsey GA, Libutti DE, O'Riordan M, Shelton JM, Storer N, Ganz J, et al. Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection. Antivir Ther 2008; 13: 715–22
   PubMed Web of Science ®Google Scholar
• Galluzzi L, Pinti M, Guaraldi G, Mussini C, Troiano L, Roat E, et al. Altered mitochondrial RNA production in adipocytes from HIV-infected individuals with lipodystrophy. Antivir Ther 2005; 10(Suppl 2)M91–9
   PubMed Web of Science ®Google Scholar
• Giralt M, Domingo P, Guallar JP, Rodriguez de la Concepcion ML, Alegre M, Domingo JC, et al. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther 2006; 11: 729–40
   PubMed Web of Science ®Google Scholar
• Mallon PW, Unemori P, Sedwell R, Morey A, Rafferty M, Williams K, et al. 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 Dis 2005; 191: 1686–96
   PubMed Web of Science ®Google Scholar
• Martin A, Smith DE, Carr A, Ringland C, Amin J, Emery S, et al. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 2004; 18: 1029–36
   PubMed Web of Science ®Google Scholar
• Moyle GJ, Sabin CA, Cartledge J, Johnson M, Wilkins E, Churchill D, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006; 20: 2043–50
   PubMed Web of Science ®Google Scholar
• McComsey GA, Paulsen DM, Lonergan JT, Hessenthaler SM, Hoppel CL, Williams VC, et al. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 2005; 19: 15–23
   PubMed Web of Science ®Google Scholar
• Cherry CL, Lal L, Thompson KA, McLean CA, Ross LL, Hernandez J, et al. Increased adipocyte apoptosis in lipoatrophy improves within 48 weeks of switching patient therapy from stavudine to abacavir or zidovudine. J Acquir Immune Defic Syndr 2005; 38: 263–7
   PubMed Web of Science ®Google Scholar
• Haubrich RH, Riddler SA, DiRienzo AG, Komarow L, Powderly WG, Klingman K, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS 2009; 23: 1109–18
   PubMed Web of Science ®Google Scholar
• Aukrust P, Müller F, Lien E, Nordøy I, Liabakk NB, Kvale D, et al. Tumor necrosis factor (TNF) system levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy: persistent TNF activation is associated with virologic and immunologic treatment failure. J Infect Dis 1999; 179: 74–82
   PubMed Web of Science ®Google Scholar
• Maagaard A, Holberg-Petersen M, Løvgården G, Holm M, Pettersen F, Kvale D. Distinct mechanisms for mitochondrial DNA loss in T and B lymphocytes from HIV-infected patients exposed to nucleoside reverse-transcriptase inhibitors and those naive to antiretroviral treatment. J Infect Dis 2008; 198: 1474–81
   PubMed Web of Science ®Google Scholar
• Sweeney LL, Brennan AM, Mantzoros CS. The role of adipokines in relation to HIV lipodystrophy. AIDS 2007; 21: 895–904
   PubMed Web of Science ®Google Scholar
• Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941–6
   PubMed Web of Science ®Google Scholar
• Addy CL, Gavrila A, Tsiodras S, Brodovicz K, Karchmer AW, Mantzoros CS. Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. J Clin Endocrinol Metab 2003; 88: 627–36
   PubMed Web of Science ®Google Scholar
• Lagathu C, Eustace B, Prot M, Frantz D, Gu Y, Bastard JP, et al. Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 2007; 12: 489–500
   PubMed Web of Science ®Google Scholar
• Lindegaard B, Keller P, Bruunsgaard H, Gerstoft J, Pedersen BK. Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients. Clin Exp Immunol 2004; 135: 273–9
   PubMed Web of Science ®Google Scholar
• Jones SP, Janneh O, Back DJ, Pirmohamed M. Altered adipokine response in murine 3T3-F442A adipocytes treated with protease inhibitors and nucleoside reverse transcriptase inhibitors. Antivir Ther 2005; 10: 207–13
   PubMed Web of Science ®Google Scholar
• Lagathu C, Kim M, Maachi M, Vigouroux C, Cervera P, Capeau J, et al. HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo. Biochimie 2005; 87: 65–71
   PubMed Web of Science ®Google Scholar
• Kuller LH, Tracy R, Belloso W, De Witt S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5: 1496–508
   Web of Science ®Google Scholar
• Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002; 359: 1026–31
   PubMed Web of Science ®Google Scholar
• Kannisto K, Sutinen J, Korsheninnikova E, Fisher RM, Ehrenborg E, Gertow K, et al. 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. AIDS 2003; 17: 1753–62
   PubMed Web of Science ®Google Scholar
• Ledru E, Christeff N, Patey O, de Truchis P, Melchior JC, Gougeon ML. Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood 2000; 95: 3191–8
   PubMed Web of Science ®Google Scholar
• Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 2000; 25: 312–21
   PubMed Web of Science ®Google Scholar
• Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS 2004; 18: 137–51
   PubMed Web of Science ®Google Scholar
• Villarroya F, Domingo P, Giralt M. Lipodystrophy in HIV 1-infected patients: lessons for obesity research. Int J Obes 2007; 12: 1–14
   Google Scholar
• Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007; 293: E444–52
   PubMed Web of Science ®Google Scholar
• Guallar JP, Gallego-Escuredo JM, Domingo JC, Alegre M, Fontdevila J, Martinez E, et al. Differential gene expression indicates that ‘buffalo hump’ is a distinct adipose tissue disturbance in HIV-1-associated lipodystrophy. AIDS 2008; 22: 575–84
   PubMed Web of Science ®Google Scholar
• Kosmiski LA, Kuritzkes DR, Lichtenstein KA, Glueck DH, Gourley PJ, Stamm ER, et al. Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AIDS 2001; 15: 1993–2000
   PubMed Web of Science ®Google Scholar
• Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002; 16: 859–63
   PubMed Web of Science ®Google Scholar
• Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2002; 16: F1–8
   PubMed Web of Science ®Google Scholar
• Levy AR, McCandless L, Harrigan PR, Hogg RS, Bondy G, Iloeje UH, et al. Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV/AIDS. Lipids Health Dis 2005; 4: 4
   PubMedGoogle Scholar
• Walli R, Goebel FD, Demant T. Impaired glucose tolerance and protease inhibitors. Ann Intern Med 1998; 129: 837–8
   PubMed Web of Science ®Google Scholar
• Brown TT, Li X, Cole SR, Kingsley LA, Palella FJ, Riddler SA, et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS 2005; 19: 1375–83
   PubMed Web of Science ®Google Scholar
• Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51: 2944–50
   PubMed Web of Science ®Google Scholar
• Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350: 664–71
   PubMed Web of Science ®Google Scholar
• Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267–73
   PubMed Web of Science ®Google Scholar
• Estrada V, Martinez-Larrad MT, Gonzalez-Sanchez JL, de Villar NG, Zabena C, Fernandez C, et al. Lipodystrophy and metabolic syndrome in HIV-infected patients treated with antiretroviral therapy. Metabolism 2006; 55: 940–5
   PubMed Web of Science ®Google Scholar
• Jones SP, Qazi N, Morelese J, Lebrecht D, Sutinen J, Yki-Jarvinen H, et al. Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens. J Acquir Immune Defic Syndr 2005; 40: 565–72
   PubMed Web of Science ®Google Scholar
• Nagy GS, Tsiodras S, Martin LD, Avihingsanon A, Gavrila A, Hsu WC, et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis 2003; 36: 795–802
   PubMed Web of Science ®Google Scholar
• Nolan D, Hammond E, James I, McKinnon E, Mallal S. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther 2003; 8: 617–26
   PubMed Web of Science ®Google Scholar
• Haugaard SB, Andersen O, Pedersen SB, Dela F, Richelsen B, Nielsen JO, et al. Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy. J Med Virol 2005; 77: 29–38
   PubMed Web of Science ®Google Scholar
• Maagaard A, Holberg-Petersen M, Torjesen PA, Bruun JN, Kvale D. Brief report: Insulin resistance is affected by increased levels of plasma lactate but not mitochondrial alterations in skeletal muscle in NRTI-exposed HIV-infected patients. HIV Clin Trials 2007; 8: 345–53
   PubMed Web of Science ®Google Scholar
• Mokrzycki MH, Harris C, May H, Laut J, Palmisano J. Lactic acidosis associated with stavudine administration: a report of five cases. Clin Infect Dis 2000; 30: 198–200
   PubMed Web of Science ®Google Scholar
• Scruggs ER, Naylor AJD. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology 2008; 82: 83–8
   PubMed Web of Science ®Google Scholar
• Hall CD, Snyder CR, Messenheimer JA, Wilkins JW, Robertson WT, Whaley RA, et al. Peripheral neuropathy in a cohort of human immunodeficiency virus-infected patients. Incidence and relationship to other nervous system dysfunction. Arch Neurol 1991; 48: 1273–4
   PubMedGoogle Scholar
• Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 2000; 14: 273–8
   PubMed Web of Science ®Google Scholar
• Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998; 19: 481–94
   PubMed Web of Science ®Google Scholar
• Chan DC. Mitochondrial dynamics in disease. N Engl J Med 2007; 356: 1707–9
   PubMed Web of Science ®Google Scholar
• Hart AM, Wilson AD, Montovani C, Smith C, Johnson M, Terenghi G, et al. Acetyl-L-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS 2004; 18: 1549–60
   PubMed Web of Science ®Google Scholar
• Herzmann C, Johnson MA, Youle M. Long-term effect of acetyl-L-carnitine for antiretroviral toxic neuropathy. HIV Clin Trials 2005; 6: 344–50
   PubMed Web of Science ®Google Scholar
• Hulgan T, Haas D, Haines JL, Ritchie MD, Robbins GK, Shafer RW, et al. Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS 2005; 19: 1341–9
   PubMed Web of Science ®Google Scholar
• Chan DC. Mitochondria: dynamic organelles in disease, aging, and development. Cell 2006; 125: 1241–52
   PubMed Web of Science ®Google Scholar
• Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D'Agati VD. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol 2001; 32: 734–40
   PubMed Web of Science ®Google Scholar
• Barrios A, Garcia-Benayas T, Gonzalez-Lahoz J, Soriano V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 2004; 18: 960–3
   PubMed Web of Science ®Google Scholar
• Verhelst D, Monge M, Meynard JL, Fouqueray B, Mougenot B, Girard PM, et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002; 40: 1331–3
   PubMed Web of Science ®Google Scholar
• Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006; 42: 283–90
   PubMed Web of Science ®Google Scholar
• Fux CA, Christen A, Zgraggen S, Mohaupt MG, Furrer H. Effect of tenofovir on renal glomerular and tubular function. AIDS 2007; 21: 1483–5
   PubMed Web of Science ®Google Scholar
• Saumoy M, Vidal F, Peraire J, Sauleda S, Vea AM, Vilades C, et al. Proximal tubular kidney damage and tenofovir: a role for mitochondrial toxicity?. AIDS 2004; 18: 1741–2
   PubMed Web of Science ®Google Scholar
• Côté HC, Magil AB, Harris M, Scarth BJ, Gadawski I, Wang N, et al. Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther 2006; 11: 79–86
   PubMed Web of Science ®Google Scholar
• Moyle G, Boffito M. Unexpected drug interactions and adverse events with antiretroviral drugs. Lancet 2004; 364: 8–10
   PubMed Web of Science ®Google Scholar
• Izzedine H, Hulot JS, Villard E, Goyenvalle C, Dominguez S, Ghosn J, et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis 2006; 194: 1481–91
   PubMed Web of Science ®Google Scholar
• Currier JS. Sex differences in antiretroviral therapy toxicity: lactic acidosis, stavudine, and women. Clin Infect Dis 2007; 45: 261–2
   PubMed Web of Science ®Google Scholar
• Lichtenstein KA, Delaney KM, Armon C, Ward DJ, Moorman AC, Wood KC, et al. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr 2003; 32: 48–56
   PubMed Web of Science ®Google Scholar
• Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 2000; 22: 911–36
   PubMed Web of Science ®Google Scholar
• Yamanaka H, Gatanaga H, Kosalaraksa P, Matsuoka-Aizawa S, Takahashi T, Kimura S, et al. Novel mutation of human DNA polymerase gamma associated with mitochondrial toxicity induced by anti-HIV treatment. J Infect Dis 2007; 195: 1419–25
   PubMed Web of Science ®Google Scholar
• Hulgan T, Tebas P, Canter JA, Mulligan K, Haas DW, Dube M, et al. Hemochromatosis gene polymorphisms, mitochondrial haplogroups, and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis 2008; 197: 858–66
   PubMed Web of Science ®Google Scholar
• Lewis W, Kohler JJ, Hosseini SH, Haase CP, Copeland WC, Bienstock RJ, et al. Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. AIDS 2006; 20: 675–84
   PubMed Web of Science ®Google Scholar
• Casula M, Bosboom-Dobbelaer I, Smolder K, Otto S, Bakker M, de Baar MP, et al. Infection with HIV-1 induces a decrease in mtDNA. J Infect Dis 2005; 191: 1468–71
   PubMed Web of Science ®Google Scholar
• Maagaard A, Holberg-Petersen M, Kvittingen EA, Sandvik L, Bruun JN. Depletion of mitochondrial DNA copies/cell in peripheral blood mononuclear cells (PBMC) in HIV-1 infected treatment-naive patients. HIV Med 2006; 7: 53–8
   PubMed Web of Science ®Google Scholar
• Miró O, Lopez S, Martinez A, Pedrol E, Milinkovic A, Deig E, et al. Mitochondrial effects of HIV infection on the peripheral blood mononuclear cells of HIV-infected patients who were never treated with antiretrovirals. Clin Infect Dis 2004; 39: 710–6
   PubMed Web of Science ®Google Scholar
• Kim MJ, Jardel C, Barthelemy C, Jan V, Bastard JP, Fillaut-Chapin S, et al. Mitochondrial DNA content: an inaccurate biomarker of mitochondrial alteration in HIV-related lipodystrophy. Antimicrob Agents Chemother 2008; 52: 1670–6
   PubMed Web of Science ®Google Scholar