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Mitochondrial toxicity associated with nucleoside reverse transcriptase inhibitor therapy

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Abstract

Nucleoside reverse transcriptase inhibitors result in a wide range of toxic side effects. These include lactic acidosis syndrome, myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, and possibly lipodystrophy. Despite the seemingly diverse nature of these side effects, all of these toxicities may be mediated by a common pathophysiologic mechanism, namely, mitochondrial toxicity resulting from nucleoside reverse transcriptase inhibitor-induced inhibition of DNA polymerase γ. This article reviews the relevant mitochondrial biology and mechanism underlying nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical manifestations of this toxicity are reviewed followed by a discussion of clinical management.

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References and Recommended Reading

  1. Wallace DC: Mitochondrial diseases in man and mouse. Science 1999, 283:1482–1487. ellent general review of mitochondrial diseases.

    Article  PubMed  CAS  Google Scholar 

  2. Brinkman K, ter Hofstede HJM, Burger DM, et al.: Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998, 12:1735–1744. Good review of NRTI-mediated mitochondrial toxicity.

    Article  PubMed  CAS  Google Scholar 

  3. Lewis W, Dalakas MC: Mitochondrial toxicity of antiviral drugs. Nat Med 1995, 1:417–422.

    Article  PubMed  CAS  Google Scholar 

  4. Baltimore D: Viral RNA-dependent DNA polymerase: RNAdependent DNA polymerase in virions of RNA tumour virses. Nature 1970, 226:1209–1211.

    Article  PubMed  CAS  Google Scholar 

  5. Balzarini J: Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Pharm World Sci 1994, 16:113–126.

    Article  PubMed  CAS  Google Scholar 

  6. Kakuda TN: Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000, 22:685–708.

    Article  PubMed  CAS  Google Scholar 

  7. Gao WY, Shirasaka T, Johns DG, et al.: Differential phosphorylation of azidothymidine, dideoxycytidine and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J Clin Invest 1993, 91:2326–2333.

    Article  PubMed  CAS  Google Scholar 

  8. Gao WY, Agbaria R, Driscoll JS, et al.: Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′3′-dideoxynucleoside analogs in resting and activated human cells. J Biol Chem 1994, 2691:12633–12638.

    Google Scholar 

  9. Chen C-H, Cheng Y-C: Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2′3′-dideoxycytidine. J Biol Chem 1989, 264:11934–11937.

    PubMed  CAS  Google Scholar 

  10. Medina DJ, Tsai C-H, Hsiung GD, et al.: Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus didoxynucleosides. Antimicrob Agents Chemother 1994, 38:1824–1828.

    PubMed  CAS  Google Scholar 

  11. Agarwal RP, Olivero OA: Genotoxicity and mitochondrial damage in human lymphocytic cells chronically exposed to 3′-azido-2′,3′-dideoxythymidine. Mutat Res 1997, 390:223–231.

    PubMed  CAS  Google Scholar 

  12. Chen CH, Vazquez PM, 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.

    PubMed  CAS  Google Scholar 

  13. Dolce V, Fiermonte G, Runswick MJ, et al.: The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. Proc Nalt Acad Sci U S A 2001, 98:2284–2288.

    Article  CAS  Google Scholar 

  14. Stacpoole PW: Lactic acidosis and other mitochondrial disorders. Metabolism 1997, 46:306–321.

    Article  PubMed  CAS  Google Scholar 

  15. Boxwell DE, Styrt BA: Lactic acidosis in patients receiving nucleoside reverse transcriptase inhibitors. Paper presented at 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco. September 26–29, 1999.

  16. Lonergan JT, Havlier D, Behling C, et al.: Hyperlactatemia in 20 patients receiving NRTI combination regimens. Paper presented at 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30–February 2, 2000.

  17. Cohen RD, Woods HF: Review: lactic acidosis revisited. Diabetes 1983, 32:181–191.

    PubMed  CAS  Google Scholar 

  18. Vrouenraets SME, Treskes M, Regez RM: Hyperlactatemia in HIV-infected patients: the role of NRTI treatment. Paper presented at 8th Conference on Retroviruses and Opportunistic Infections. Chicago. February 4–8, 2001.

  19. Boubaker K, Sudre P, Flepp M, et al.: Hyperlactatemia and antiretroviral therapy in the Swiss HIV Cohort Study (SHCS). Paper presented at 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30–February 2, 2000.

  20. Peters BS, Winer J, Landom DN: Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Am J Med 1993, 86:5–15.

    CAS  Google Scholar 

  21. Simpson DM, Slasor P, Dafni U, et al.: Analysis of myopathy in a placebo-controlled zidovudine trial. Muscle Nerve 1997, 43:971–976.

    Google Scholar 

  22. Simpson DM, Katzenstein DA, Hughes MD, et al.: Neuromuscular function in HIV infection: analysis of a placebo-controlled combination antiretroviral trial. AIDS 1998, 12:2425–2432.

    Article  PubMed  CAS  Google Scholar 

  23. Arnaudo E, Dalakas M, Shanske S, et al.: Depletion of muscle mitochondrial DNA in AIDS patients with zidovudineinduced myopathy. The Lancet 1991, 337:508–510.

    Article  CAS  Google Scholar 

  24. Herskowitz A, Willoughby SB, Baughman KL: Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection. Ann Intern Med 1992, 116:311–313.

    PubMed  CAS  Google Scholar 

  25. Lipshultz SE, Orav EJ, Sanders SP, et al.: Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine. N Engl J Med 1992, 327:1260–1265.

    Article  PubMed  CAS  Google Scholar 

  26. Lipshultz SE, Easley KA, Orav EJ, et al.: Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med 2000, 343:759–766.

    Article  PubMed  CAS  Google Scholar 

  27. Wilde MI, Langtry HD: Zidovudine: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993, 46:515–578.

    PubMed  CAS  Google Scholar 

  28. Lutton JD, Mathew A, Levere RD, et al.: Role of heme metabolism in AZT-induced bone marrow toxicity. Am J Hematol 1990, 35:1–5.

    Article  PubMed  CAS  Google Scholar 

  29. Gallicchio VS, Hughes NK, Tse KF: Comparison of dideoxynucleoside drugs (DDI and zidovudine) and induction of hematopoietic toxicity using normal human bone marrow cells in vitro. Int J Immunopharmacol 1993, 15:263–268.

    Article  PubMed  CAS  Google Scholar 

  30. Luster MI, Rosenthal GJ, Cao W, et al.: Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection. Int J Immunopharmacol 1991, 13(Suppl 1):99–107.

    Article  PubMed  CAS  Google Scholar 

  31. Faraj A, Fowler DA, Bridges EG, et al.: Effects of 2′,3′-dideoxynucleosides on proliferation and differentiation of human pluripotent progenitors in liquid culture and their effects on mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994, 38:924–930.

    PubMed  CAS  Google Scholar 

  32. Fichtenbaum CJ, Clifford DB, Powderly WG: Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995, 10:169–174.

    Article  PubMed  CAS  Google Scholar 

  33. Simpson DM, Tagliati M: Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995, 9:153–161.

    PubMed  CAS  Google Scholar 

  34. Moyle GJ, Sadler M: Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998, 19:481–494.

    Article  PubMed  CAS  Google Scholar 

  35. Moore RD, Wong WM, Keruly JC, et al.: Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 2000, 14:273–278.

    Article  PubMed  CAS  Google Scholar 

  36. Brew B, Tisch S, Law M: Lactate concentrations distinguish between nucleoside neuropathy and HIV distal symmetrical sensory polyneuropathy. Paper presented at 8th Conference on Retroviruses and Opportunistic Infections. Chicago. February 4–8, 2001.

  37. Dassopoulos T, Ehrenpreis ED: Acute pancreatitis in human immunodeficiency virus-infected patients: a review. Am J Med 1999, 107:78–84.

    Article  PubMed  CAS  Google Scholar 

  38. Moore RD, Keruly JC, Chaisson RE: Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS 2001, 15:617–620.

    Article  PubMed  CAS  Google Scholar 

  39. Foli A, Benvenuto F, Piccinini G, et al.: Direct analysis of mitochondrial toxicity of antiretroviral drugs. AIDS 2001, 15:1687–1694.

    Article  PubMed  CAS  Google Scholar 

  40. Lake-Bakaar G, Mazzoccoli V, Dickman K, et al.: Differential effects of nucleoside analogs on oxidative phosphorylation in human pancreatic cells. Dig Dis Sci 2001, 46:1853–1863.

    Article  PubMed  CAS  Google Scholar 

  41. Brinkman K, Smeitink J, Romijn J, et al.: 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. Hypothesis of NRTI-mediated mitochondrial toxicity as an explanation for HAART-associated lipodystrophy.

    Article  PubMed  CAS  Google Scholar 

  42. Kakuda T, Brundage RC, Anderson PL, et al.: Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy [letter]. AIDS 1999, 13:2311–2312.

    Article  PubMed  CAS  Google Scholar 

  43. Klopstock T, Naumann M, Seibel F, et al.: Mitochondrial DNA mutations in multiple symmetric lipomatosis. Mol Cell Biochem 1994, 174:271–275.

    Article  Google Scholar 

  44. Naumann M, Kiefer R, Toyka KV, et al.: Mitochondrial dysfunction with myoclonus epilepsy and ragged-red fibers point mutation in nerve, muscle, and adipose tissue of a patient with multiple symmetric lipomatosis. Muscle Nerve 1997, 20:833–839.

    Article  PubMed  CAS  Google Scholar 

  45. Becker-Wegerich P, Steuber M, Olbrisch R, et al.: Defects of mitochondrial respiratory chain in multiple symmetric lipomatosis. Arch Dermatol Res 1998, 290:652–655.

    Article  PubMed  CAS  Google Scholar 

  46. Saint-Marc T, Partisani M, Poizot-Martin I, et al.: A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999, 13:1659–1667.

    Article  PubMed  CAS  Google Scholar 

  47. Mallal J, John M, Moor CB, et al.: Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000, 14:1309–1316.

    Article  PubMed  CAS  Google Scholar 

  48. Lichtenstein K, Ward D, Delaney K, et al.: Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 2001, 15:1389–1398.

    Article  PubMed  CAS  Google Scholar 

  49. 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-F32.

    Article  PubMed  CAS  Google Scholar 

  50. Walker UA, Bickel M, Lütke Volksbeck SI, et al.: Decrease of mitochondrial DNA content in adipose tissue of HIV-1 infected patients treated with NRTIs. Antiviral Ther 2000, 5(Suppl 5):5.

    Google Scholar 

  51. Shikuma CM, Hu N, Milne C, et al.: Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV infected individuals with peripheral lipoatrophy. AIDS 2001, 15:1801–1809.

    Article  PubMed  CAS  Google Scholar 

  52. Mallal SA, Hammond EL, Martin A, et al.: Mitochondrial DNA depletion, assessed by real-time PCR-based quantitative assay, in subcutaneous fat of HIV-infected patients: evidence for a role in the etiology of fat wasting. Paper presented at 4th International Conference on Nutrition and HIV Infection/2nd European Workshop on Lipodystrophy. Cannes, France. April 19–21, 2001.

  53. Mallal S, Nolan D, John M, et al.: Light and electron microscopy findings in subcutaneous fat in antiretroviral treated and HIV-infected patients. Paper presented at XIII International AIDS Conference. Durban, South Africa. July 9–14, 2000.

  54. Blanche S, Rouzioux C, Mandelbrot L, et al.: Zidovudine-lamivudine for prevention of mother to child HIV-1 transmission. French National Study. Paper presented at 6th Conference on Retroviruses and Opportunistic Infections. Chicago. January 31–February 4, 1999.

  55. Blanche S, Tardieu M, Rustin P, et al.: Persistent mitochondrial dysfunction and perinatal exposure to anti-retroviral nucleoside analogues. Lancet 1999, 354:1084–1089.

    Article  PubMed  CAS  Google Scholar 

  56. Gerschenson M, Poirier MC: Fetal patas monkeys sustain mitochondrial toxicity as a result of in utero zidovudine exposure. Ann NY Acad Sci 2000, 918:269–281.

    Article  PubMed  CAS  Google Scholar 

  57. Ewings EL, Gerschenson M, St Claire MC, et al.: Genotoxic and functional consequences of tran splacental zidovudine exposure in fetal monkey brain mitochondria. J Acquir Immune Defic Syndr 2000, 24:100–105.

    PubMed  CAS  Google Scholar 

  58. Hanson C, Frederick M, McIntosh K: Evaluation of living uninfected children for mitochondrial defects: Women and Infants Transmission Study. Paper presented at 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30–February 2, 2000.

  59. McIntosh K: Mitochondrial toxicity of perinatally administered zidovudine. Paper presented at 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30–February 2, 2000.

  60. Peters BS, Winer J, Landon DN, et al.: Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Q J Med 1993, 86:5–15.

    PubMed  CAS  Google Scholar 

  61. 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.

    Article  PubMed  CAS  Google Scholar 

  62. Brinkman K: Special lecture: current developments of mitochondrial toxicity, focusing on lactic acidosis and hyperlactatemia and treatment. Paper presented at 4th International Conference on Nutrition and HIV Infection/2nd European Workshop on Lipodystrophy. Cannes, France. April 19–21, 2001.

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Shikuma, C.M., Shiramizu, B. Mitochondrial toxicity associated with nucleoside reverse transcriptase inhibitor therapy. Curr Infect Dis Rep 3, 553–560 (2001). https://doi.org/10.1007/s11908-001-0094-4

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