Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: A looming obstacle for long-term antiretroviral therapy?

Current Opinion in Infectious Diseases

Volumn 13, Issue 1, 2000, Pages 5-11

  Brinkman, Kees ^a   Kakuda, Thomas N ^b  

^a ONZE LIEVE VROUWE GASTHUIS   (Netherlands)

^b UNIVERSITY OF MINNESOTA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABACAVIR; ACETYLCARNITINE; ACETYLCYSTEINE; ACETYLSALICYLIC ACID; ALCOHOL; ALPHA TOCOPHEROL; AMIODARONE; ASCORBIC ACID; BIOTIN; CARNITINE; CHLORAMPHENICOL; DIDANOSINE; FOLIC ACID; HYDROXYUREA; LAMIVUDINE; NICOTINIC ACID; NONSTEROID ANTIINFLAMMATORY AGENT; PANTOTHENIC ACID; RIBOFLAVIN; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAVUDINE; TETRACYCLINE; THIAMINE; THIOCTIC ACID; UBIDECARENONE; UNINDEXED DRUG; VALPROIC ACID; ZALCITABINE; ZIDOVUDINE;

DISORDERS OF MITOCHONDRIAL FUNCTIONS; DRUG ANTAGONISM; DRUG CYTOTOXICITY; DRUG INHIBITION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LACTIC ACIDOSIS; LIPODYSTROPHY; LONG TERM CARE; NONHUMAN; PHOSPHORYLATION; REVIEW; RISK FACTOR;

EID: 0034033584     PISSN: 09517375     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001432-200002000-00002     Document Type: Review

References (58)

1. 1 Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1:417-422. See reference [2••].
2. 2 Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998, 12:1735-1744. This an excellent review of NRTI-induced mitochondrial toxicity.
3. 3 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; 354:1112-1115. A hypothesis on the link between lipodystrophy and NRTI-induced mitochondrial dysfunction.
4. 4 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; 38:2743-2749.
5. 5 Gray NM, Marr CL, Penn CR, Cameron JM, Bethell RC. The intracellular phosphorylation of (-)-2′-deoxy-3′-thiacytidine (3TC) and the incorporation of 3TC 5′-monophosphate into DNA by HIV-1 reverse transcriptase and human DNA polymerase gamma. Biochem Pharmacol 1995; 50:1043-1051.
6. 6 Medina DJ, Tsai CH, Hsiung GD, Cheng YC. Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides. Antimicrob Agents Chemother 1994; 38:1824-1828.
7. 7 Chen CH, Vazquez Padua M, Cheng YC. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 1991; 39:625-628.
8. 8 Chinnery PF, Howell N, Andrews RM, Turnbull DM. Clinical mitochondrial genetics. J Med Genet 1999; 36:425-436.
9. 9 Chariot P, Drogou I, de Lacroix-Szmania I, Eliezer-Vanerot MC, Chazaud B, Lombes A, et al. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 1999; 30:156-160. A case report of mitochondrial dysfunction in a patient treated with ZDV. Skeletal muscle biopsy showed ragged red fibers with cytochrome c oxidase deficiency. Liver biopsy at autopsy showed massive macro-and micro-vesicular steatosis. mtDNA was markedly reduced in muscle and liver biopsies, but not in myocardium and kidney.
10. 10 Gasnault J, Pinganaud C, Kousignian P, Lacroix C, Slama A, Delfraissy J-F. Subacute ascendant polyneuropathy revealing a nucleoside-induced mitochondrial cytopathy. 7th European Conference on Clinical Aspects and Treatment of HIV-infection, 1999 [Abstract 1081].
11. 11 Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354:1084-1089. This paper is the first to report the potential mitochondrial toxicity occurring in neonates exposed to NRTI in utero.
12. 12 Sundar K, Suarez M, Banogon PE, Shapiro JM. Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: report of two patients and review of the literature. Crit Care Med 1997; 25:1425-1430.
13. 13 Brinkman K, ter Hofstede HJ. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: lactic acidosis, risk factors and therapeutic options. AIDS Rev 1999; 1:141-148. This paper reviews NRTI-induced lactic acidosis and its management.
14. 14 Fortgang IS, Belitsos PC, Chaisson RE, Moore RD. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol 1995; 90:1433-1436.
15. 15 Boxwell DE, Styrt BA. Lactic acidosis (LA) in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs). 39th Interscience Conference on Antimicrobal Agents and Chemotherapy, San Francisco, 1999 [Abstract 1284].
16. 16 Maulin L, Gerard Y, de la Tribonniere X, Amiel C, Valette M, Baclet V, et al. Emerging complication of antiretroviral therapy: symptomatic hyperlactatemia. 39th Interscience Conference on Antimicrobal Agents and Chemotherapy, San Fransisco, 1999 [Abstract 1285].
17. 17 Lonergan JT, Behling C, Pfander H, Hassanein TI, Mathews WC. Hyperlactatemia and hepatic abnormalities in ten HIV-infected patients taking multiple nucleoside analogs [Abstract 348]. Clin Infect Dis 1999; 29:1022.
18. 18 Martinez E, Gatell JM. Metabolic complications and body fat redistribution in HIV-1 infected individuals: the fat redistribution syndrome. Curr Opin Infect Dis 1999; 12:13-19. An excellent review of the fat redistribution syndrome with a focus on PI involvement.
19. 19 Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353:2093-2099.
20. 20 Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomatosis associated with protease inhibitors. Lancet 1997; 350:1596.
21. 21 Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999; 13:1659-1667. This paper describes the development of lipoatrophy in patients receiving long-term NRTI therapy. Preliminary evidence of mitochondrial dysfunction was noted in three patients.
22. 22 Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. 'Buffalo hump' in men with HIV-1 infection. Lancet 1998; 351:867-870. A case series of eight patients developing 'buffalo hump'-four were receiving two NRTI and a PI and the other four only received NRTI.
23. 23 Gervasoni C, Ridolfo AL, Trifirò G, Santambrogio S, Norbatio G, Musicco M, et al. Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 1999; 13:465-471. This paper is the first to report an association of fat redistribution syndrome with NRTI.
24. 24 Madge S, Kinloch de Loes S, Mercey D, Johnson MA, Weller IVD. Lipodystrophy in patients naive to protease inhibitors. AIDS 1999; 13:735-737.
25. 25 Aldeen T, Wells C, Hay P, Davidson F, Lau R. Lipodystrophy associated with nevirapine-containing antiretroviral therapies. AIDS 1999; 13:865-867.
26. 26 Saint-Marc T, Touraine JL. 'Buffalo hump' in HIV-1 infection. Lancet 1998; 352:319-320.
27. 27 Carr A, Miller J, Law M, Cooper DA. A syndrome of lipodystrophy (LD), lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue reverse transcriptase inhibitor therapy: a contribution to PI-related LD syndrome. Antiviral Ther 1999; 4 (Suppl. 2):19-20.
28. 28 Mallal S, John M, Moore C, James I, Mckinnon E. Protease inhibitors and nucleoside analogue reverse transcriptase inhibitors interact to cause subcutaneous fat wasting in patients with HIV infection. Antiviral Ther 1999; 4 (Suppl. 2):28-29.
29. 29 Polo R, Verdejo J, Gonzalez-Muñoz M, Gomez-Cano M, Martinez-Garrido S, Martinez-Rodriguez S, Gonzalez-Lahoz J. Lipodystrophy related to NRT inhibitors in HAART therapy. 39th Interscience Conference on Antimicrobal Agents and Chemotherapy, San Francisco, 1999 [Abstract 1302].
30. 30 Ward D, Delaney K, Moorman A, Lichtenstein K, Palella F, Young B, et al. Clinical factors related to lipodystrophy severity in the HIV Outpatient Study (HOPS). 39th Interscience Conference on Antimicrobal Agents and Chemotherapy, San Francisco, 1999 [Abstract 1299].
31. 31 Saint-Marc T, Touraine JL, The effects of discontinuing stavudine therapy on clinical and metabolic abnormalities in patients suffering from lipodystrophy. AIDS 1999; 13:2188-2189. This paper provides preliminary evidence to suggest that switching from d4T to 2DV improves fat redistribution.
32. 32 Polo R, Verdejo J, Gonzalez-Muñoz M, Gomez-Cano M, Martinez-Garrido S, Martinez-Rodriguez S, Gonzalez-Lahoz J. Switch to AZT+3TC improves lipodystrophy signs in the presence of protease inhibitors. 39th Interscience Conference on Antimicrobal Agents and Chemotherapy, San Francisco, 1999 [Abstract 1306]. This paper also provides preliminary evidence to suggest that switching from d4T to ZDV improves fat redistribution.
33. 33 Teplitsky V, Halabe A. Fat distribution in AIDS. N Engl J Med 1999; 340:969-970. These authors note the similarity between fat redistribution syndrome in persons infected with HIV and the disease known as multiple symmetric lipomatosis (Madelung's disease).
34. 34 Berkovic SF, Andermann F, Shoubridge EA, Carpenter S, Robitaille Y, Andermann E, et al. Mitochondrial dysfunction in multiple symmetrical lipomatosis. Ann Neurol 1991; 29:566-569.
35. 35 Klopstock T, Naumann M, Schalke B, Bischof F, Seibel P, Kottlors M, et al. Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA. Neurology 1994; 44:862-866.
36. 36 Becker-Wegerich P, Steuber M, Olbrisch R, Ruzicka T, Auburger G, Hofhaus G. Defects of mitochondrial respiratory chain in multiple symmetric lipomatosis. Arch Dermatol Res 1998; 290:652-655.
37. 37 Larsson NG, Tulinius MH, Holme E, Oldfors A, Andersen O, Wahlstrom J, Aasly J. Segregation and manifestations of the mtDNA tRNA (Lys) A → G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet 1992; 51:1201-1212.
38. 38 Silvestri G, Ciafaloni E, Santorelli FM, Shanske S, Servidei S, Graf WD, et al. Clinical features associated with the A → G transition at nucleotide 8344 of mtDNA ('MERRF mutation'). Neurology 1993; 43:1200-1206.
39. 39 Mathews CE, Berdanier CD. Noninsulin-dependent diabetes mellitus as a mitochondrial genomic disease. Proc Soc Exp Biol Med 1998; 219:97-108.
40. 40 Rotig A, Bonnefont JP, Munnich A. Mitochondrial diabetes mellitus. Diabetes Metab 1996; 22:291-298.
41. 41 Gerbitz KD, Gempel K, Brdiczka D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 1996; 45:113-126.
42. 42 Kakuda TN, Brundage RC, Anderson PL, Fletcher CV. Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. AIDS 1999; 13:2311-2312. A hypothesis on the link between lipodystrophy and NRTI-induced mitochondrial dysfunction, and its role in the induction of apoptosis in peripheral adipocytes.
43. 43 Lori F. Hydroxyurea and HIV: 5 years later - from antiviral to immune-modulating effects. AIDS 1999; 13:1433-1442.
44. 44 Thompson M, Gable J, Lawrence J, Rimland D, McCarthy W. A retrospective case-control study to determine if the addition of hydroxyurea to regimens that contain ddl or d4T or ddl and d4T increases the risk of developing peripheral neuropathy in HIV infected individuals [Abstract 57]. Antiviral Ther 1998; 3:54-55.
45. 45 Barry M, Clarke S, Mulcahy F, Back D, Hydroxyurea-induced neurotoxicity in HIV disease. AIDS 1999; 13:1592-1594. A case report of a patient developing confusion, hallucinations and hostility when treated with abacavir, ddl, saquinavir, and hydroxyurea. The symptoms resolved after hydroxyurea was discontinued.
46. 46 Weissman SB, Sinclair GI, Green CL, Fissell WH. Hydroxyurea-induced hepatitis in human immunodeficiency virus-positive patients. Clin Infect Dis 1999; 29:223-224. A case report of two patients developing liver failure on a ddl, d4T, hydroxyurea-containing regimen; the fourth agent was nelfinavir in one case and ritonavir/ saquinavir in the other.
47. 47 Goodrich J, Khardori N. Hydroxyurea toxicity in human immunodeficiency virus-positive patients. Clin Infect Dis 1999; 29:692-693.
48. 48 Scholte HR. The biochemical basis of mitochondrial diseases. J Bioenerg Biomembr 1988; 20:161-191.
49. 49 Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J Hepatol 1997; 26 (Suppl. 2):43-53.
50. 50 Barbaro G, Di Lorenzo G, Asti A, Ribersani M, Belloni G, Grisorio B, et al. Hepatocellular mitochondrial alterations in patients with chronic hepatitis C: ultrastructural and biochemical findings. Am J Gastroenterol 1999; 94:2198-2205. These authors observed mitochondrial abnormalities in liver biopsies obtained from persons with chronic HCV infection. HCV genotype 1b in particular was associated with decreased mtDNA.
51. 51 Rust C, Gores GJ. Does hepatitis C cause liver injury by pathways associated with mitochondrial dysfunction? Am J Gastroenterol 1999; 94:2003-2005. In an accompanying editorial, these authors suggest a hypothesis for HCV-induced hepatitis.
52. 52 van Vooren JP, Farber CM, Schneider E, Delforge ML, Liesnard C, Biston P, Cogan E. Safety of antiprotease therapy after two episodes of lactic acidosis in an HIV-infected patient. 4th International Congress on Drug Therapy in HIV Infection, Glasgow, 1998 [Abstract P162].
53. 53 de la Asuncion JG, del Olmo ML, Sastre J, Millan A, Pellin A, Pallardo FV, Vina J. AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins. J Clin Invest 1998; 102:4-9.
54. 54 Campos Y, Huertas R, Lorenzo G, Bautista J, Gutierrez E, Aparicio M, et al. Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondrial myopathy. Muscle Nerve 1993; 16:150-153.
55. 55 Famularo G, Moretti S, Marcellini S, Trinchieri V, Tzantzoglou S, Santini G, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS 1997; 11:185-190.
56. 56 Fouty B, Frerman F, Reves R. Riboflavin to treat nucleoside analogue induced lactic acidosis. Lancet 1998; 352:291-292.
57. 57 Luzatti R, Del Bravo P, Di Perri G, Luzzani A, Concia E. Riboflavine and severe lactic acidosis. Lancet 1999, 353:901-902.
58. 58 Lenzo NP, Garas BA, French MA. Hepatic steatosis and lactíc acidosis associated with stavudine treatment in an HIV patient: a case report. AIDS 1997; 11:1294-1296.