HIV-Associated Antiretroviral Toxic Neuropathy (ATN): A Review of Recent Advances in Pathophysiology and Treatment

Simpson D.M. , & Tagliati M. Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology 1995; 9: 153–161.

Hall C.D. , Snyder C.R. , Messenheimer J.A. , Wilkins J.W. , Robertson W.T. , Whaley R.A. , & Robertson K.R. Peripheral neuropathy in a cohort of human immunodeficiency virus-infected patients. Incidence and relationship to other nervous system dysfunction. Archives of Neurology 1991; 48: 1273–1274.

Kieburtz K. , Simpson D. , Yiannoutsos C. , Max M.B. , Hall C.D. , Ellis R.J. , Marra C.M. , McKendall R. , Singer E. , Dal Pan G.J. , Clifford D.B. , Tucker T. , & Cohen B. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998; 51: 1682–1688.

Moyle G.J. , & Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Safety 1998; 19: 481–94.

Moore R.D. , Wong W.M. , Keruly J.C. , & McArthur J.C. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 2000; 14: 273–278.

Brinkman K. , ter Hofstede H.J. , Burger D.M. , Smeitink J.A. , & Koopmans P.P. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway AIDS 1998; 12: 1735–1744.

Simpson D.M. , Haidich A.B. , Schifitto G. , Yiannoutsos C.T. , Geraci A.P. , McArthur J.C. , & Katzenstein D.A. Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levels. AIDS 2002; 16: 407–412.

La Spina I. , Porazzi D. , Maggiolo F. , Bottura P. , & Suter F. Gabapentin in painful HIV-related neuropathy: a report of 19 patients, preliminary observations. European Journal of Neurology 2001; 8: 71–75.

Simpson D.M. , McArthur J.C. , Olney R. , Clifford D. , So Y. , Baird B.J. , Barrett P. , & Hammer A.E. Lamotrigine for HIV-associated painful peripheral sensory neuropathies: a placebo controlled trial. Neurology 2003; 60: 1508–1514.

McArthur J.C. , Yiannoutsos C. , Simpson D.M. , Adornato B.T. , Singer E.J. , Hollander H. , Marra C. , Rubin M. , Cohen B.A. , Tucker T. , Navia B.A. , Schifitto G. , Katzenstein D. , Rask C. , Zaborski L. , Smith M.E. , Shriver S. , Millar L. , Clifford D.B. , & Karalnik I.J. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 2000; 54: 1080–1088.

Pozniak A. , Gazzard B. , Anderson J. , Babiker A. , Churchill D. , Collins S. , Fisher M. , Johnson M. , Khoo S. , Leen C. , Loveday C. , Moyle G. , Nelson M. , Peters B. , Phillips A. , Pillay D. , Wilkins E. , Williams I. , & Youle M. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy: BHIVA Writing Committee -on behalf of the BHIVA Executive Committee. July 2003 [cited June 2005]. Available from: http://www.bhiva.org/guidelines/2003/hiv/index.html.

Chen C.H. , Vazquez-Padua M. , & Cheng Y.C. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Molecular Pharmacology 1991; 39: 625–628.

Keilbaugh S.A. , Prusoff W.H. , & Simpson M.V. The PC12 cell as a model for studies of the mechanism of induction of peripheral neuropathy by anti-HIV-1 dideoxynucleoside analogs. Biochemical Pharmacology 1991; 42: R5–R8.

Lewis W. , & Dalakas M.C. Mitochondrial toxicity of antiviral drugs. Nature Medicine 1995; 1: 417–422.

McCarthy B.G. , Hsieh S.T. , Stocks A. , Hauer P. , Macko C. , Cornblath D.R. , Griffin J.W. , & McArthur J.C. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 1995; 45: 1848–1855.

Polydefkis M. , Yiannoutsos C.T. , Cohen B.A. , Hollander H. , Schifitto G. , Clifford D.B. , Simpson D.M. , Katzenstein D. , Shriver S. , Hauer P. , Brown A. , Haidich A.B. , Moo L. , & McArthur J.C. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 2002; 58: 115–119.

Hahn K. , Arendt G. , Braun J.S. , von Giesen H.J. , Husstedt I.W. , Maschke M. , Straube M.E. , & Schielke E. ; German Neuro-AIDS Working Group. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. Journal of Neurology 2004; 251: 1260–1266.

Paice J.A. , Ferrans C.E. , Lashley F.R. , Shott S. , Vizgirda V. , & Pitrak D. Topical capsaicin in the management of HIV-associated peripheral neuropathy. Journal of Pain & Symptom Management 2000; 19: 45–52.

Simpson D. , Brown S. , Sampson J. , Estanislao L. , Vilahu C. , Ramanathan S. , Jermano J. , & von Stein T. Novel high-concentration capsaicin patch for the treatment of painful HIV - an associated distal symmetrical polyneuropathy: results of an open label trial. 11th Conference on Retroviruses & Opportunistic Infections. 8–11 February 2004, San Francisco, CA, USA. Abstract 490.

McArthur J.C. , Yiannoutsos C. , Simpson D.M. , Adornato B.T. , Singer E.J. , Hollander H. , Marra C. , Rubin M. , Cohen B.A. , Tucker T. , Navia B.A. , Schifitto G. , Katzenstein D. , Rask C. , Zaborski L. , Smith M.E. , Shriver S. , Millar L. , Clifford D.B. , & Karalnik I.J. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 2000; 54: 1080–1088.

Schifitto G. , Yiannoutsos C. , Simpson D.M. , Adornato B.T. , Singer E.J. , Hollander H. , Marra C.M. , Rubin M. , Cohen B.A. , Tucker T. , Koralnik I.J. , Katzenstein D. , Haidich B. , Smith M.E. , Shriver S. , Millar L. , Clifford D.B. , & McArthur J.C. ; AIDS Clinical Trials Group Team 291. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology 2001; 57: 1313–1316.

Apfel S.C. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? International Review of Neurobiology 2002; 50: 393–413.

Bremer J. The role of carnitine in intracellular metabolism. Journal of Clinical Chemistry & Clinical Biochemistry 1990; 28: 297–301.

Manfridi A. , Forloni G.L. , Arrigoni-Martelli E. , & Mancia M. Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF. International Journal of Developmental Neuroscience 1992; 10: 321–329.

Hart A.M. , Wiberg M. , & Terenghi G. Pharmacological enhancement of peripheral nerve regeneration in the rat by systemic acetyl-L-carnitine treatment. Neuroscience Letters 2002; 334: 181–185.

Virmani M.A. , Biselli R. , Spadoni A. , Rossi S. , Corsico N. , Calvani M. , Fattorossi A. , De Simone C. , & Arrigoni-Martelli E. Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacological Research 1995; 32: 383–389.

Hart A.M. , Wiberg M. , Youle M. , & Terenghi G. Systemic acetyl-L-carnitine eliminates sensory neuronal loss after peripheral axotomy: a new clinical approach in the management of peripheral nerve trauma. Experimental Brain Research 2002; 145: 182–189.

Sima A.A. , Ristic H. , Merry A. , Kamijo M. , Lattimer S.A. , Stevens M.J. , & Greene D.A. Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding worcester rat. Journal of Clinical Investigation 1996; 97: 1900–1907.

Onofrj M. , Fulgente T. , Melchionda D. , Marchionni A. , Tomasello F. , Salpietro F.M. , Alafaci C. , De Sanctis E. , Pennisi G. , Bella R. , Ventura F. , & Morganti A. L-acetylcarnitine as a new therapeutic approach for peripheral neuropathies with pain. International Journal of Clinical Pharmacology Research 1995; 15: 9–15.

Famularo G. , De Simone C. , & Cifone G. Carnitine stands on its own in HIV infection treatment. Archives of Internal Medicine 1999; 159: 1143–1144.

De Grandis D. , & Minardi C. Acetyl-L-carnitine (levacarnine) in the treatment of diabetic neuropathy. A long-term randomized, double-blind, placebo controlled study. Drugs in R&D 2002; 3: 223–231.

Scarpini E. , Sacilotto G. , Baron P. , Cusini M. , & Scarlato G. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. Journal of the Peripheral Nervous System 1997; 2: 250–252.

Hart A.M. , Wilson A.D. , Montovani C. , Smith C. , Johnson M. , Terenghi G. , & Youle M. Acetyl-L-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS 2004; 18: 1549–1560.

Calvani M. , & Arrigoni-Martelli E. Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion. International Journal of Tissue Reactions 1999; 21: 1–6.

Tesco G. , Latorraca S. , Piersanti P. , Piacentini S. , Amaducci L. , & Sorbi S. Protection from oxygen radical damage in human diploid fibroblasts by acetyl-L-carnitine. Dementia 1992; 3: 58–60.

Peluso G. , Benatti P. , Nicolai R. , Reda E. , & Calvani M. (1998) Carnitine system and insulin resistance. In Insulin Resistance, Metabolic Disease & Diabetic Complications; pp. 259–274. Edited by Crepaldi G. , Tiengo A. , & Del Prato S. . Elsevier.

Fernandez E. , Pallini R. , Gangitano C. , Del Fa A. , Sangiacomo C.O. , Sbriccoli A. , Ricoy J.R. , & Rossi G.F. Effects of L-carnitine, L-acetylcarnitine and gangliosides on the regeneration of the transected sciatic nerve in rats. Neurological Research 1989; 11: 57–62.

Kano M. , Kawakami T. , Hori H. , Hashimoto Y. , Tao Y. , Ishikawa Y. , & Takenaka T. Effects of ALCAR on the fast axoplasmic transport in cultured sensory neurons of strep-tozotocin-induced diabetic rats. Neuroscience Research 1999; 33: 207–213.

Stevens M.J. , Lattimer S.A. , Feldman E.L. , Helton E.D. , Millington D.S. , Sima A.A. , & Greene D.A. Acetyl-L-carnitine deficiency as a cause of altered nerve myoinositol content, Na, K-ATPase activity and motor conduction velocity in the streptozotocin-diabetic rat. Metabolism 1996; 45: 865–872.

De Grandis D. , Santoro L. , & Di Benedetto P. L-acetylcarnitine in the treatment of patients with peripheral neuropathies. Clinical Drug Investigation 1995; 10: 317–322.

Giammusso B. , Morgia G. , Spampinto A. , & Motta M. Improved pallesthetic sensitivity of pudendal nerve in impotent diabetic patients treated with acetyl-L-carnitine. Archivio Italiano di Urologia 1996; 10: 185–187.

Famularo G. , Moretti S. , Marcellini S. , Trinchieri V. , Tzantzoglou S. , Santini G. , Longo A. , & De Simone C. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS 1997; 11: 185–190.