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

Scandinavian Journal of Infectious Diseases

Volumn 41, Issue 11-12, 2009, Pages 808-817

  Maagaard, Anne ^a,b   Kvale, Dag ^a,b  

^a OSLO UNIVERSITY HOSPITAL   (Norway)

^b UNIVERSITY OF OSLO   (Norway)

Author keywords

[No Author keywords available]

Indexed keywords

ABACAVIR; ADEFOVIR DIPIVOXIL; ANTIRETROVIRUS AGENT; DIDANOSINE; EFAVIRENZ; INDINAVIR; INTERLEUKIN 6; LACTIC ACID; LAMIVUDINE; LOPINAVIR; NELFINAVIR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; RIBAVIRIN; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAVUDINE; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; TENOFOVIR; TENOFOVIR DISOPROXIL; TUMOR NECROSIS FACTOR ALPHA; UNCOUPLING PROTEIN 1; ZALCITABINE; ZIDOVUDINE;

BODY COMPOSITION; BODY FAT; CD4+ T LYMPHOCYTE; DIABETES MELLITUS; DRUG EFFICACY; DRUG INHIBITION; DYSLIPIDEMIA; FANCONI RENOTUBULAR SYNDROME; GLOMERULUS FILTRATION RATE; HEPATITIS B; HEPATITIS C; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERLACTATEMIA; INSULIN RESISTANCE; KIDNEY FAILURE; LACTATE BLOOD LEVEL; LACTIC ACIDOSIS; LIPID COMPOSITION; LIPOATROPHY; LONG TERM CARE; MITOCHONDRIAL TOXICITY; MYOPATHY; NEPHROTOXICITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PERIPHERAL NEUROPATHY; POPULATION; REVIEW; SIDE EFFECT; SKELETAL MUSCLE;

HIV INFECTIONS; HUMANS; MITOCHONDRIA; REVERSE TRANSCRIPTASE INHIBITORS; TIME FACTORS;

EID: 70450172623     PISSN: 00365548     EISSN: 16511980     Source Type: Journal    
DOI: 10.3109/00365540903186181     Document Type: Review

References (140)

1. 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.
2. 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.
3. 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.
4. 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.
5. Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte A, El-SadrW, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007;/356:/1723-35.
6. 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.
7. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mito chondrial toxicity induced by nucleoside-analogue reversetranscriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;/ 354:/1112-5.
8. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995;/1:/417-22.
9. 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.
10. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by longterm zidovudine therapy. N Engl J Med 1990;/322:/ 1098-1105 (Pubitemid 20149526)
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Larsson NG, Oldfors A. Mitochondrial myopathies. Acta Physiol Scand 2001;/171:/385-93.
17. Graziewicz MA, Longley MJ, Copeland WC. DNA polymerase gamma in mitochondrial DNA replication and repair. Chem Rev 2006;/106:/383-405.
18. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000;/22:/685-708.
19. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007;/87:/ 99-163. (Pubitemid 46209992)
20. Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 2007;/8:/405-13.
21. Wallace DC. Mitochondrial diseases in man and mouse. Science 1999;/283:/1482-8.
22. Shuster RC, Rubenstein AJ, Wallace DC. Mitochondrial DNA in anucleate human blood cells. Biochem Biophys Res Commun 1988;/155:/1360-5.
23. 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.
24. Smeitink J, Van Den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2001;2:342-352
25. Shapiro TA, Englund PT. The structure and replication of kinetoplast DNA. Annu Rev Microbiol 1995;/49:/117-43.
26. Falkenberg M, Larsson NG, Gustafsson CM. DNA replication and transcription in mammalian mitochondria. Annu Rev Biochem 2007;/76:/679-99.
27. Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Disc 2003;/2:/812-22.
28. 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. (Pubitemid 34157656)
29. 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. (Pubitemid 37373231)
30. 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.
31. Moyle G. Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism? Drug Saf 2000;/23:/467-81. (Pubitemid 32001511)
32. Lim SE, Copeland WC. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem 2001;/276:/23616-23.
33. 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.
34. 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.
35. Barile M, Valenti D, Quagliariello E, Passarella S. Mitochondria as cell targets of AZT (zidovudine). Gen Pharmacol 1998;/31:/531-8.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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 HIVinfected patients. J Acquir Immune Defic Syndr 2002;/29:/ 117-121
43. 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.
44. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS 2001;/15:/795-7.
45. 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.
46. Miró O?, López SP, 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.
47. 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;41:721-728
48. 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.
49. 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.
50. 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:/ 1290-1296
51. 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 reversetranscriptase inhibitors: a case-control study. Clin Infect Dis 2003;/36:/1324-8.
52. Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004;/38:/ e79-80.
53. Butt AA. Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. AIDS Read 2003;/13:/ 344-348
54. De Mendoza C, Soriano V. The role of hepatitis C virus (HCV) in mitochondrial DNA damage in HIV/HCVcoinfected individuals. Antivir Ther 2005;/10(Suppl 2):/ M109-15.
55. 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.
56. 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.
57. 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.
58. John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, et al. Chronic hyperlactatemia in HIVinfected patients taking antiretroviral therapy. AIDS 2001;/ 15:/717-23.
59. 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.
60. 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.
61. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000;/356:/1423-30.
62. Lichtenstein KA. Redefining lipodystrophy syndrome: risks and impact on clinical decision making. J Acquir Immune Defic Syndr 2005;/39:/395-400.
63. 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.
64. 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.
65. 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.
66. 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.
67. McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion 2004;/4:/111-8.
68. 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:/ 1329-1338
69. 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.
70. 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:/ 715-722
71. 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.
72. 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.
73. 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.
74. 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:/ 1029-1036
75. 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:/ 2043-2050
76. 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.
77. 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.
78. 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.
79. 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.
80. Maagaard A, Holberg-PetersenM, Løvgarden G, Holm M, Pettersen F, Kvale D. Distinct mechanisms for mitochondrial DNA loss in Tand 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.
81. Sweeney LL, Brennan AM, Mantzoros CS. The role of adipokines in relation to HIV lipodystrophy. AIDS 2007;/ 21:/895-904.
82. 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.
83. 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.
84. 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.
85. Lindegaard B, Keller P, Bruunsgaard H, Gerstoft J, Pedersen BK. Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIVinfected patients. Clin Exp Immunol 2004;/135:/273-9.
86. 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.
87. 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.
88. 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;5:1496-1508
89. Bastard JP, Caron M, Vidal H, Jan V, AuclairM, 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.
90. 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.
91. Ledru E, Christeff N, Patey O, de Truchis P, Melchior JC, Gougeon ML. Alteration of tumor necrosis factor-alpha Tcell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood 2000;/95:/3191-8.
92. 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.
93. Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS 2004;/18:/ 137-151
94. Villarroya F, Domingo P, Giralt M. Lipodystrophy in HIV 1-infected patients: lessons for obesity research. Int J Obes 2007;/12:/1-14.
95. 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.
96. 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.
97. 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.
98. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002;/16:/859-63.
99. Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K, et al. Indinavir acutely inhibits insulinstimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2002;/16:/F1-8.
100. 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.
101. Walli R, Goebel FD, Demant T. Impaired glucose tolerance and protease inhibitors. Ann Intern Med 1998;/129:/837-8.
102. 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.
103. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002;/51:/2944-50.
104. 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.
105. 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:/ 267-273
106. 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.
107. 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.
108. 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.
109. 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.
110. 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.
111. 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 HIVinfected patients. HIV Clin Trials 2007;/8:/345-53.
112. 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.
113. Scruggs ER, Naylor AJD. Mechanisms of zidovudineinduced mitochondrial toxicity and myopathy. Pharmacology 2008;82:83-88
114. 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.
115. 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:/ 273-278
116. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998;/19:/481-94.
117. Chan DC. Mitochondrial dynamics in disease. N Engl J Med 2007;/356:/1707-9.
118. 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.
119. Herzmann C, Johnson MA, Youle M. Long-term effect of acetyl-L-carnitine for antiretroviral toxic neuropathy. HIV Clin Trials 2005;/6:/344-50.
120. 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. (Pubitemid 41800669)
121. Chan DC. Mitochondria: dynamic organelles in disease, aging, and development. Cell 2006;/125:/1241-52.
122. 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:/ 734-740
123. Barrios A, Garcia-Benayas T, Gonzalez-Lahoz J, Soriano V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 2004;/18:/960-3.
124. 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.
125. 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.
126. Fux CA, Christen A, Zgraggen S, Mohaupt MG, Furrer H. Effect of tenofovir on renal glomerular and tubular function. AIDS 2007;/21:/1483-5.
127. 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.
128. 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 HIVinfected patients on highly active antiretroviral therapy. Antivir Ther 2006;/11:/79-86.
129. Moyle G, Boffito M. Unexpected drug interactions and adverse events with antiretroviral drugs. Lancet 2004;/364:/ 8-10.
130. 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.
131. Currier JS. Sex differences in antiretroviral therapy toxicity: lactic acidosis, stavudine, and women. Clin Infect Dis 2007;/45:/261-2.
132. 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.
133. Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 2000;/22:/911-36. (Pubitemid 30671584)
134. 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.
135. 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:/ 858-866
136. 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.
137. 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.
138. 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.
139. Miró O? , Lopez SP, 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.
140. 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:/ 1670-1676