Free Standard AU & NZ Shipping For All Book Orders Over $80!
Register      Login
Sexual Health Sexual Health Society
Publishing on sexual health from the widest perspective
Shopping Cart: ( empty )
You are here: Home > Journals > SH > SH04016
REVIEW
Contents Vol 2(1)

Mitochondrial toxicity of nucleoside analogues: mechanism, monitoring and management

Catherine L. Cherry A B C D , Luxshimi Lal A and Steven L. Wesselingh A B C
+ Author Affiliations
- Author Affiliations

A Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, Vic. 3001, Australia.

B Infectious Diseases Unit, The Alfred Hospital, PO Box 315, Prahran, Vic. 3181, Australia.

C Department of Medicine, Monash University, Alfred Hospital Campus, Prahran, Vic. 3181, Australia.

D Corresponding author. Email: kate.cherry@med.monash.edu.au

Sexual Health 2(1) 1-11 https://doi.org/10.1071/SH04016
Submitted: 19 May 2004  Accepted: 22 November 2004   Published: 22 March 2005

Abstract

Nucleoside analogues (NRTIs) are potent antiretroviral medications and are central to effective highly active antiretroviral therapy (HAART). Their intended action is to inhibit HIV reverse transcriptase. Nucleoside analogues also inhibit replication of mitochondrial DNA, and the pathogenesis of many of the toxicities associated with HAART is thought to be NRTI-induced mitochondrial dysfunction. Individuals with HIV infection may be particularly susceptible to clinically significant mitochondrial toxicity due to possible effects of HIV itself on mitochondria. At present there is no reliable method of detecting subclinical mitochondrial toxicity in patients exposed to NRTIs. Clinical awareness of this problem is therefore important to ensure the early detection of significant side effects and to allow timely consideration of changing therapy in those affected. There is no proven, effective therapy for NRTI-associated mitochondrial toxicity other than ceasing the implicated agent, and even with this strategy, resolution of symptoms may be incomplete. Similarly, there are no established methods for preventing mitochondrial toxicity in those on therapy including NRTIs. Micronutrients may have a role, but further study is needed to clarify optimal prevention as well as monitoring strategies.

Additional keyword: HIV.


References


[1] Correll P,  Law M,  McDonald A,  Cooper D,  Kaldor J. HIV disease progression in Australia in the time of combination antiretroviral therapies. Med J Aust 1998; 169 469–72.
| PubMed |

[2] Egger M,  Hirschel B,  Francioli P,  Sudre P,  Wirz M,  Flepp M, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV Cohort Study. BMJ 1997; 315 1194–9.
| PubMed |

[3] Mouton Y,  Alfandari S,  Valette M,  Cartier F,  Dellamonica P,  Humbert G, et al. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. Federation National des Centres de Lutte contre le SIDA. AIDS 1997; 11 101–5.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[4] Palella F,  Delaney K,  Moorman A,  Loveless M,  Fuhrer J,  Satten G, 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.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[5] Torres R,  Barr M. Impact of combination therapy for HIV infection on inpatient census. N Engl J Med 1997; 336 1531–2.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[6] Stewart G. You've gotta have HAART. Med J Aust 1998; 169 456–7.
| PubMed |

[7] Rachlis A,  Zarowny D. Group CHTNAW. Guidelines for antiretroviral therapy for HIV infection. Can Med Assoc J 1998; 158(4): 496–505.


[8] Carpenter CC,  Cooper DA,  Fischl MA,  Gatell JM,  Gazzard BG,  Hammer SM, et al. Antiretroviral therapy in adults. Updated recommendations of the International AIDS Society — USA Panel. JAMA 2000; 283(3): 381–90.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[9] Brinkman K,  ter Hofstede J,  Burger D,  Smeitink J,  Koopmans P. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12 1735–44.
| PubMed |

[10] Brinkman K,  Smeitink J,  Romijn J,  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.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[11] Lewis W,  Dalakas M. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1 417–22.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[12] Chen C,  Vazquez-Padua M,  Cheng Y. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 1991; 39 625–8.
| PubMed |

[13] Morris A,  Carr A. HIV nucleoside analogues: new adverse effects on mitochondria? (Editorial). Lancet 1999; 354 1046–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[14] Kakuda T,  Brundage R,  Anderson P,  Fletcher C. Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy (letter). AIDS 1999; 13 2311–2.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[15] Chen C,  Cheng Y. 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 11 934–7.
| PubMed |

[16] Struble K,  Pratt R,  Gitterman S. Toxicity of antiretroviral agents. Am J Med 1997; 102 65–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[17] Kakuda T. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22 685–708.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[18] Lewis W,  Day BJ,  Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an intergrated cellular perspective. Nat Rev Drug Discov 2003; 2(10): 812–22.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[19] Wallace D. Mitochondrial diseases in man and mouse. SCIENCE 1999; 283 1482–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[20] Shapiro AV. Inborn and induced defects of mitochondria. Arch Neurol 1998; 55 1293–6.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[21] Simon D,  Johns D. Mitochondrial disorders: clinical and genetic features. Annu Rev Med 1999; 50 111–27.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[22] Mallal S,  Nolan D,  Witt C,  Masel G,  Martin A,  Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359(9308): 727–32.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[23] Stein DE,  Moore KH. Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy 2001; 21(1): 11–34.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[24] Chattha G,  Arieff AI,  Cary C,  Tierney LM. Lactic acidosis complicating the acquired immunodeficiency syndrome. [Brief Report] Ann Intern Med 1993; 118(1): 37–9.
| PubMed |

[25] Morgello S,  Wolfe D,  Godfrey E,  Feinstein R,  Tagliati M,  Simpson DM. Mitochondrial abnormalities in human immunodeficiency virus-associated myopathy. Acta Neuropathol (Berl) 1995; 90(4): 366–74.
| PubMed |

[26] Phenix B,  Badley A. Influence of mitochondrial control of apoptosis on the pathogenesis, complications and treatment of HIV infection. Biochimie 2002; 84(2–3): 251–64.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[27] Badley A,  Roumier T,  Lum J,  Kroemer G. Mitochondrion-mediated apoptosis in HIV-1 infection. Trends Pharmacol Sci 2003; 24(6): 298–305.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[28] Cossarizza A,  Mussini C,  Mongiardo N,  Borghi V,  Sabbatini A,  DeRienzo B, et al. Mitochondria alterations and dramatic tendency to undergo apoptosis in peripheral blood lymphocytes during acute HIV syndrome. AIDS 1997; 11 19–26.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[29] Thompson K,  McArthur JC,  Wesselingh SL. Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol 2001; 49(6): 745–52.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[30] Petit F,  Arnoult D,  Lelievre J,  Moutouh-de Parseval L,  Hance A,  Schneider P, et al. Productive HIV-1 infection of primary CD4+ T cells induces mitochondrial membrane permeabilization leading to a caspase-independent cell death. J Biol Chem 2002; 277(2): 1477–87.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[31] Genini D,  Sheeter D,  Rought S,  Zaunders J,  Susin S,  Kroemer G, et al. HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism. FASEB J 2001; 15 1– .
| Crossref | GoogleScholarGoogle Scholar |

[32] Macho A,  Castedo M,  Marchetti P,  Aguilar J,  Decaudin D,  Zamzami N, et al. Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers. Blood 1995; 86(7): 2481–7.
| PubMed |

[33] Plymale D,  Tang D,  Comardelle A,  Fermin C,  Lewis D,  Garry R. Both necrosis and apoptosis contribute to HIV-1-induced killing of CD4 cells. AIDS 1999; 13 1827–39.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[34] So Y,  Holtzman D,  Abrams D,  Olney R. Peripheral neuropathy associated with Acquired Immunodeficiency Syndrome — prevalence and clinical features from a population-based survey. Arch Neurol 1988; 45(Sept): 945–8.
| PubMed |

[35] Griffin J,  Crawford T,  Tyor W,  Glass J,  Price D,  Cornblath D, et al. Predominantly sensory neuropathy in AIDS: distal axonal degeneration and unmyelinated fiber loss. Neurology 1991; 41(Suppl 1): 374.


[36] Cherry C, McArthur J, Costello K, Wolley I, Mijch A, Wesslingh S. Increasing prevalence of neuropathy in the era of highly active antiretroviral therapy (HAART). In: 9th Conference on retroviruses and opportunistic infections. Seattle, USA; 2002.

[37] Schilling BE,  Nelson DR,  Proctor JE,  Diamond SS,  Kaul S,  Hawkins HC. The nonclinical toxicologic profile of stavudine. Current Therapeutic Research 1995; 56(3): 201–18.
| Crossref | GoogleScholarGoogle Scholar |

[38] Tsai C,  Follis K,  Yarnall M,  Blakley G. Toxicity and efficacy of 2′,3′-dideoxycytidine in clinical trials of pigtailed macaques infected with simian retrovirus type 2. Antimicrob Agents Chemother 1989; 33(11): 1908–14.
| PubMed |

[39] Mallon PWG, Unemori P, Sedwel IR, Williams K, Merlin K, Kelleher A, et al. Nucleoside Reverse Transcriptase Inhibitors decrease monocyte mitochondrial gene transcription, an effect that persists 6 weeks after discontinuation of the drugs. In: Australasian Society for HIV Medicine annual meeting. Canberra, Australia; 2004.

[40] 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 1084–9.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[41] Gerschenson M,  Nguyen V,  Ewings E,  Ceresa A,  Shaw J,  St Clair M, et al. Mitochondrial toxicity in fetal Erythrocebus pata monkeys exposed transplacentally to zidovudine plus lamivuidne. AIDS Res Hum Retroviruses 2004; 20(1): 91–100.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[42] Poirier M,  Divi R,  Al-Harthi L,  Olivero O,  Nguyen V,  Walker B, et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J Acquir Immune Defic Syndr 2003; 33(2): 175–83.
| PubMed |

[43] Stojanov S,  Wintergerst U,  Belchohradsky B,  Rolinski B. Mitochondrial and peroxisomal dysfunction following perinatal exposure to antiretroviral drugs. AIDS 2000; 14(11): 1669.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[44] Alimenti A,  Burdge DR,  Ogilvie GS,  Money DM,  Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J 2003; 22 782–8.
| PubMed |

[45] Barret B,  Tardieu M,  Rustin P,  Lacroix C,  Chabrol B,  Desguerre I, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17 1769–85.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[46] Bulterys M,  Nesheim S,  Abrams E,  Palumbo P,  Farley J,  Lampe M, et al. Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study. Ann NY Acad Sci 2000; 918 212–21.
| PubMed |

[47] The Perinatal Safety Review Working Group Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs; absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000; 25 261–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[48] Poulton J,  Lyall H,  Taylor G,  Williams GT. HIV-1 therapy and fetal mitochondrial dysfunction. Lancet 1999; 354 2081–2.
| PubMed |

[49] Connor EM,  Sperling RS,  Gelber R,  Kiselev P,  Scott G,  O'Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331(18): 1173–80.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[50] Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS 2001; 15 795–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[51] John M,  Mallal SA. Hyperlactatemia syndromes in people with HIV infection. Curr Opin Infect Dis 2002; 15 23–9.
| PubMed |

[52] Noguera A,  Fortuny C,  Sanchez E,  Artuch R,  Vilaseca MA,  Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment. Pediatr Infect Dis J 2003; 22 778–82.
| PubMed |

[53] Marceau G,  Sapin V,  Jacomet C,  Ughetto S,  Cormerais L,  Regagnon C, et al. Frequency, risk factors, and outcome of hyperlactatemia in HIV-positive persons: implications for the management of treated patients. Clin Chem 2003; 49(7): 1154–62.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[54] Moyle GJ,  Datta D,  Mandalia S,  Morlese J,  Ashoe D,  Gazzard BG. Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS 2002; 16 1341–9.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[55] Harris M,  Chan KJ,  Tesiorowski AM,  Hogg RS,  Rosenberg FM,  Yan CC, et al. Random venous lactate levels among HIV-positive patients on antiretroviral therapy (letter). J Acquir Immune Defic Syndr 2002; 31 448–50.
| PubMed |

[56] Huynh TK,  Luttichau HR,  Roge B,  Gerstoft J. Natural history of hyperlactataemia in Human Immunodeficiency Virus-1-infected patients during highly active antiretroviral therapy. Scand J Infect Dis 2003; 35 62–6.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[57] 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; 15 795–7.
| PubMed |

[58] 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(11): 1931–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[59] Datta D,  Moyle GJ,  Mandalia S,  Gazzard BG. Matched case-control study to evaluate risk factors for hyperlactataemia in HIV patients on antiretroviral therapy. HIV Med 2003; 4 311–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[60] Garcia-Benayas T,  Blanco F,  de la Cruz JJ,  Soriano V,  Gonzallez-Lahoz J. Replacing stavudine by abacavir reduces lactate levels and may improve lipoatrophy (research letter). AIDS 2003; 17(6): 921–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[61] Delggado J,  Harris M,  Tesiorowski AM,  Montaner JS. Symptomatic elevations of lactic acid and their response to treatment manipulation in human immunodeficiency virus-infected persons: a case series. Clin Infect Dis 2001; 33(12): 2072–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[62] Tesiorowski M,  Harris M,  Chan KJ,  Thompson CR,  Montaner JS. Anaerobic threshold and random venous lactate levels among HIV-positive patients on antiretroviral therapy (letter). J Acquir Immune Defic Syndr 2002; 31 250–1.
| PubMed |

[63] Hammond EL,  Sayer D,  Nolan D,  Walker UA,  de Ronde A,  Montaner JS, et al. Assessment of precision and concordance of quantitative mitochondrial DNA assays: a collaborative international quality assurance study. J Clin Virol 2003; 27 97–110.


[64] Nolan D,  Hammond EL,  Martin A,  Taylor L,  Herrmann S,  McKinnon EJ, et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nuclesoide reverse transcriptase inhibitor therapy. AIDS 2003; 17 1329–38.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[65] Cherry CL, Nolan D, James I, Mallal S, French M, Hammond EL, et al. Longitudinal associations between antiretroviral treatments and quantification of tissue mitochondrial DNA from ambulatory subjects with HIV infection. In: 10th Conference on retroviruses and opportunistic infections. Boston, USA; 2003.

[66] Hoy J, Gahan M, Carr A, Lewin S, Smith D, Cooper D, et al. Changes in mitochondrial DNA in PBMCs from patients with lipoatrophy randomized to switch to Abacavir or continue thymidine analogue-containing ARV regimens. In: 10th Conference on retroviruses and opportunistic infections. Boston, USA; 2003.

[67] Boyd M, Bien D, Ruxrungtham K, Carr A, Chomchey N, Ubolyam S, et al. Reversal of mitochondrial DNA and RNA depletion in patients switched to indinavir/ritonavir 800/100mg bid and efavirenz 600 mg qd after failing NRTI combination therapy: a prospective, 48 week substudy of HIV-NAT 009. In: International AIDS Society. Bangkok, Thailand; 2004.

[68] Petersen E,  Ramirez-Ronda C,  Hardy W,  Schwartz R,  Sacks H,  Follansbee S, et al. Dose-related activity of stavudine in patients infected with human immunodeficiency virus. J Infect Dis 1995; 171((Suppl 2)): S131–9.
| PubMed |

[69] Blum A,  Dal Pan G,  Feinberg J,  Raines C,  Mayjo B,  Cornblath D, et al. Low-dose zalcitabine-related toxic neuropathy: frequency, natural history, and risk factors. Neurology 1996; 46 999–1003.
| PubMed |

[70] Carr A,  Workman C,  Smith D,  Hoy J,  Hudson J,  Doong N, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002; 288(2): 207–15.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[71] Moyle GJ,  Baldwin C,  Langroudi B,  Mandalia S,  Gazzard BG. A 48-week randomized, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr 2003; 33(1): 22–8.
| PubMed |

[72] McComsey G,  Ward D,  Hessenthaler S,  Sension M,  Shalit P,  Lonergan J, et al. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Clin Infect Dis 2004; 38(2): 263–70.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[73] Vujovic O. Initiation of antiretroviral therapy in the naive patient. In Hoy J, Lewin S, editors. HIV management in Australasia a guide for clinical care. Sydney: ASHM; 2003

[74] Mallal S,  John M,  Moore C,  James I,  McKinnon E. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000; 14(10): 1309–16.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[75] White A. Mitochondrial toxicity and HIV therapy. Sex Transm Infect 2001; 77(3): 158–73.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[76] Joly V,  Flandre P,  Meiffredy V,  Leturque N,  Havel M,  Aboulker J-P, et al. Increased risk of lipoatrophy under stavudind in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002; 16 2447–54.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[77] Moore RD,  Wong W-ME,  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.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[78] Moore RD,  Keruly JC,  Chaisson RE. Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS 2001; 15 617–20.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[79] 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; 10 169–74.
| PubMed |

[80] Simpson D, Estanislao L, Marcus K, Truffa M, McArthur J, Lucey B, et al. HIV-associated Neuromuscular Weakness Syndrome. In: 10th Conference on retroviruses and opportunistic infections. Boston, USA; 2003.

[81] Fleischer R,  Boxwell D,  Sherman K. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004; 38(8): 79–80.
| Crossref | GoogleScholarGoogle Scholar |

[82] Moretti S,  Famularo G,  Marcellini S,  Boschini A,  Santini G,  Trinchieri V, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Redox Signal 2002; 4(3): 391–403.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[83] Hart A, Terenghi G, Johnson M, Youle M. L-acetyl carnitine therapy increases cutaneous innervation and improves symptoms in antiretroviral related HIV peripheral neuropathy. In: First international workshop on clinical pharmacology. Noordwijk, Netherlands; 2003.

[84] Rosenfeldt F,  Mijch A,  McCrystal G,  Sweeney C,  Pepe S,  Nicholls M,  Dennett X. Skeletal Myopathy associated with nucleoside reverse transcriptase inhibitor therapy: potential benefit of coenzyme Q10 therapy. Int J STD and AIDS 2005;


[85] Dalton SD,  Rahimi AR. R RA. Emerging role of riboflavin in the treatment of nucleoside analogue-induced type B lactic acidosis. AIDS Patient Care STDS 2001; 15(12): 611–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[86] Seidlin M,  Lambert J,  Dolin R,  Valentine F. Pancreatitis and pancreatic dysfunction in patients taking DDI. AIDS 1992; 6 831–5.
| PubMed |

[87] Hoy J,  Lewin S. HIV management in Australasia. A guide for clinical care. Sydney: Australasian Society for HIV Medicine; 2003 

[88] Martinez E,  Milinkovic A,  de Lazzari E,  Ravasi G,  Blanco J,  Larrousse M, et al. Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults. Lancet 2004; 364(9428): 65–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[89] Yarchoan R,  Perno C,  Thomas R,  Klecker R,  Allain J,  Wills R, et al. Phase 1 studies of 2′,3′-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988; 331(8577): 76–81.
| Crossref | GoogleScholarGoogle Scholar |

[90] Berger A,  Arezzo J,  Schaumbureg H,  Skowron G,  Merigan T,  Bozette S, et al. 2′,3′-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients. Neurology 1993; 43(2): 358–62.
| PubMed |

[91] Browne M,  Mayer K,  Chafee S,  Dudley M,  Posner M,  Steinberg S, et al. 2′,3′-didehydro-3′-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. J Infect Dis 1993; 167(1): 21–9.
| PubMed |

[92] Simpson DM,  Tagliati M. Nucleoside analogue-associated peripheral neuropathy in Human Immunodeficiency Virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 9 153–61.
| PubMed |

[93] Lambert J,  Seidlin M,  Reichmann R,  Plank C,  Laverty M,  Morse G, et al. 2′,3′-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. N Engl J Med 1990; 322(19): 1333–40.
| PubMed |

[94] Kelleher T,  Cross A,  Dunkle L. Relation of peripheral neuropathy to HIV treament in four randomized trials including didanosine. Clin Ther 1999; 21(7): 1182–92.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[95] Lamperth L,  Dalakas MC,  Dagani F,  Anderson J,  Ferrari R. Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model. Lab Invest 1991; 65(6): 742–51.
| PubMed |

[96] Dalakas MC,  Illa I,  Pezeshkpour G,  Laukaitis J,  Cohen B,  Griffin J. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990; 322(16): 1098–105.
| PubMed |

[97] Lonergan J,  Behling C,  Pfander H,  Hassaneln T,  Mathews W. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis 2000; 31 162–6.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[98] Gerard Y,  Maulin L,  Yazdanpanah Y,  De La Tribonniere X,  Amiel C,  Maurage C-A, et al. Symptomatic hyperlactatemia: an emertging complication of antiretroviral therapy. AIDS 2000; 14 2723–30.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[99] Miller KD,  Cameron M,  Wood LV,  Dalakas MC,  Kovacs JA. Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases. Ann Intern Med 2000; 133 192–6.
| PubMed |

[100] Arenas-Pinto A,  Grant A,  Edwards S,  Wellar I. Lactic acidosis in HIV infected patients: a systematic review of published cases. Sex Transm Infect 2003; 79 340–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[101] Fortgang I,  Belitsos P,  Chaisson RE,  Moore RD. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol 1995; 90(9): 1433–6.
| PubMed |

[102] Carr A,  Miller J,  Law M,  Cooper D. 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.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[103] Simpson D,  Estanislao L,  Evans S,  McArthur J,  Marcus K,  Truffa M, et al. HIV-associated neuromuscular weakness syndrome. AIDS 2004; 18(10): 1403–12.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[104] Romanelli F,  Empey K,  Pomeroy C. Macrocytosis as an indicator of medication (zidovudine) adherence in patients with HIV infection. AIDS Patient Care STDS 2002; 16(9): 405–11.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[105] Martin G,  Blazes D,  Mayers D,  Spooner K. Stavudine-induced macrocytosis during therapy for human immunodeficiency virus infection. Clin Infect Dis 1999; 29 459–60.
| PubMed |

[106] Cote HC,  Brumme ZL,  Craib KJ,  Math M,  Alexander CS,  Wynhoven B, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002; 346(11): 811–20.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[107] McComsey G,  Tan D-J,  Lederman M,  Wilson E,  Wong L-J. Analysis of the mitochondrial DNA genome in the peripheral blood leukocytes of HIV-infected patients with or without lipoatrophy. AIDS 2002; 16(4): 513–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[108] Cote HC, Yip B, Chan JW, Hogg RS, Harrigan PR, et al. Preserved mitochondrial/nuclear DNA ratios in peripheral blood cells from HIV-infected individuals on stavudine-sparing regimens. In: 14th International AIDS conference. Barcelona, Spain; 2002.

[109] Cote HC,  Yip B,  Asselin JJ,  Chan JW,  Hogg RS,  Harrigan PR, et al. Mitochondrial : nuclear DNA ratios in peipheral blood cells from Human Immunodeficiency Virus-infected patients who received selected HIV antiretroviral drug regimens (brief report). J Infect Dis 2003; 187(12): 1972–6.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[110] Lopez S, Miro O, Martinez E, Rodriguez B, Milinkovic A, Predol E, et al. Effects of different first-line HAART regimens on the content and function of lymphocyte mitochondria of HIV-infected patients without lipodystrophy. In: 14th International AIDS conference. Barcelona, Spain; 2002.

[111] Petit C,  Mathez D,  Barthelemy C,  Leste-Lasserre T,  Naviaux RK,  Sonigo P, et al. Quantitation of blood lymphocyte mitochondrial DNA for the monitoring of antiretroviral drug-induced mitochondrial DNA depletion. J Acquir Immune Defic Syndr 2003; 33 461–9.
| PubMed |

[112] Hammond EL, Nolan DA, McKinnon E, Mallal S. No evidence of mitochondrial DNA depletion in peripheral white blood cells after three to 12 months of HAART. In: 14th International AIDS conference. Barcelona, Spain; 2002.

[113] van der Valk M, Casula M, Ruiter J, Kujik C, van Eck-Smit B, Weverling G, et al.. Relation between use of nucleoside reverse transcriptase inhibitors, mitochondrial DNA depletion, and severity of lipoatrophy: results from a randomized trial comparing stavudine and zidovudine-based antiretroviral therapy. In: 10th Conference on retroviruses and opportunistic infections. Boston, USA; 2003.

[114] Hoy J,  Gahan M,  Carr A,  Smith D,  Lewin S,  Wesselingh S, et al. Changes in mitochondrial DNA in PBMCs from patients with HIV lipoatrophy randomized to abacavir. J Infect Dis 2004; 190(4): 688–92.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[115] Shikuma CM,  Hu N,  Milne C,  Yosi 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.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[116] Walker UA,  Bickel M,  Volksbeck S,  Ketelsen U-P,  Schofer H,  Setzer B, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue from HIV-infected patients. J Acquir Immune Defic Syndr 2002; 29 117–21.
| PubMed |

[117] Zaera MG,  Miro O,  Pedrol E,  Soler A,  Picon M,  Cardellach F, et al. Mitochondrial involvement in antiretroviral therapy-related lipodystrophy. AIDS 2001; 15 1643–51.
| Crossref | GoogleScholarGoogle Scholar | PubMed |