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CNS Drugs

, Volume 28, Issue 2, pp 131–145 | Cite as

Neurological and Psychiatric Adverse Effects of Antiretroviral Drugs

  • Michael S. Abers
  • Wayne X. Shandera
  • Joseph S. Kass
Review Article

Abstract

Antiretroviral drugs are associated with a variety of adverse effects on the central and peripheral nervous systems. The frequency and severity of neuropsychiatric adverse events is highly variable, with differences between the antiretroviral classes and amongst the individual drugs in each class. In the developing world, where the nucleoside reverse transcriptase inhibitor (NRTI) stavudine remains a commonly prescribed antiretroviral, peripheral neuropathy is an important complication of treatment. Importantly, this clinical entity is often difficult to distinguish from human immunodeficiency virus (HIV)-induced peripheral neuropathy. Several clinical trials have addressed the efficacy of various agents in the treatment of NRTI-induced neurotoxicity. NRTI-induced neurotoxicity is caused by inhibition of mitochondrial DNA polymerase. This mechanism is also responsible for the mitochondrial myopathy and lactic acidosis that occur with zidovudine. NRTIs, particularly zidovudine and abacavir, may also cause central nervous system (CNS) manifestations, including mania and psychosis. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is perhaps the antiretroviral most commonly associated with CNS toxicity, causing insomnia, irritability and vivid dreams. Recent studies have suggested that the risk of developing these adverse effects is increased in patients with various cytochrome P450 2B6 alleles. Protease inhibitors cause perioral paraesthesias and may indirectly increase the relative risk of stroke by promoting atherogenesis. HIV integrase inhibitors, C–C chemokine receptor type 5 (CCR5) inhibitors and fusion inhibitors rarely cause neuropsychiatric manifestations.

Keywords

Human Immunodeficiency Virus Zidovudine West Nile Virus Efavirenz Didanosine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

No sources of funding were used in the process of writing this manuscript. The authors have no conflicts of interest to disclose.

References

  1. 1.
    Brew BJ, Dore G. Decreasing incidence of CNS AIDS defining events associated with antiretroviral therapy. Neurology. 2000;55:1424.PubMedGoogle Scholar
  2. 2.
    Lipsky JJ. Zalcitabine and didanosine. Lancet. 1993;341:30–2.PubMedGoogle Scholar
  3. 3.
    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 (dideoxycytidine). Lab Invest. 2001;81:1537–44.PubMedGoogle Scholar
  4. 4.
    Brinkman K, ter Hofstede HJ, Burger DM, et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998;12:1735–44.PubMedGoogle Scholar
  5. 5.
    Keswani SC, Pardo CA, Cherry CL, Hoke A, McArthur JC. HIV-associated sensory neuropathies. AIDS. 2002;16:2105–17.PubMedGoogle Scholar
  6. 6.
    Vivoli E, Di Cesare Mannelli L, Salvicchi A, et al. Acetyl-l-carnitine increases artemin level and prevents neurotrophic factor alterations during neuropathy. Neuroscience. 2010;167:1168–74.PubMedGoogle Scholar
  7. 7.
    Famularo G, Moretti S, Marcellini S, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS. 1997;11:185–90.PubMedGoogle Scholar
  8. 8.
    Simpson DM, Katzenstein D, Haidich B, et al. Plasma carnitine in HIV-associated neuropathy. AIDS. 2001;15:2207–8.PubMedGoogle Scholar
  9. 9.
    Kallianpur AR, Hulgan T. Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy. Pharmacogenomics. 2009;10:623–37.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst. 2001;6:14–20.PubMedGoogle Scholar
  11. 11.
    Moore RD, Wong WE, 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;14:273–8.PubMedGoogle Scholar
  12. 12.
    Kelleher T, Cross A, Dunkle L. Relation of peripheral neuropathy to HIV treatment in four randomized clinical trials including didanosine. Clin Ther. 1999;21:1182–92.PubMedGoogle Scholar
  13. 13.
    Brew BJ, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV neuropathy. AIDS. 2003;17:1094–6.PubMedGoogle Scholar
  14. 14.
    Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf. 1998;19:481–94.PubMedGoogle Scholar
  15. 15.
    Phillips TJ, Cherry CL, Cox S, et al. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS ONE. 2010;5:e14433.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology. 2003;60:1508–14.PubMedGoogle Scholar
  17. 17.
    Youle M, Osio M. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl l-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med. 2007;8:241–50.PubMedGoogle Scholar
  18. 18.
    Valcour V, Yeh TM, Bartt R, et al. Acetyl-l-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection. HIV Med. 2009;10:103–10.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Shaikh S, Ta C, Basham AA, Mansour S. Leber hereditary optic neuropathy associated with antiretroviral therapy for human immunodeficiency virus infection. Am J Ophthalmol. 2001;131:143–5.PubMedGoogle Scholar
  20. 20.
    Luke C, Cornely OA, Fricke J, et al. Late onset of Leber’s hereditary optic neuropathy in HIV infection. Br J Ophthalmol. 1999;83:1194.Google Scholar
  21. 21.
    Warner JE, Ries KM. Optic neuropathy in a patient with AIDS. J Neuroophthalmol. 2001;21:92–4.PubMedGoogle Scholar
  22. 22.
    Luzhansky JZ, Pierce AB, Hoy JF, Hall AJ. Leber’s hereditary optic neuropathy in the setting of nucleoside analogue toxicity. AIDS. 2001;15:1588–9.PubMedGoogle Scholar
  23. 23.
    Mackey DA, Fingert JH, Luzhansky JZ, et al. Leber’s hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus. Eye. 2003;17:312–7.PubMedGoogle Scholar
  24. 24.
    Colebunders R, Dipraetere K, Van Wanzeele P, Van Gehuchten S. Deafness caused by didanosine. Eur J Clin Microbiol Infect Dis. 1998;17:214–5.PubMedGoogle Scholar
  25. 25.
    Simdon J, Watters D, Bartlett S, Connick E. Ototoxicity associated with use of nucleoside analog reverse transcriptase inhibitors: a report of 3 possible cases and review of the literature. Clin Infect Dis. 2001;32:1623–7.PubMedGoogle Scholar
  26. 26.
    Rey D, L’Heritier A, Lang JM. Severe ototoxicity in a healthcare worker who received postexposure prophylaxis with stavudine, lamivudine, and nevirapine after occupational exposure to HIV. Clin Infect Dis. 2002;34:417–8.Google Scholar
  27. 27.
    Schouten JT, Lockhart DW, Rees TS, et al. A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naïve people. BMC Infect Dis. 2006;6:28.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Khoza-Shangase K. Highly active antiretroviral therapy: does it sound toxic? J Pharm Bioallied Sci. 2011;3:142–53.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Bektas D, Martin GK, Stagner BB, et al. Noise-induced hearing loss in mice treated with antiretroviral drugs. Hear Res. 2008;239:69–78.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Marra CM, Wechkin HA, Longstreth WT Jr, et al. Hearing loss and antiretroviral therapy in patients infected with HIV-1. Arch Neurol. 1997;54:407–10.PubMedGoogle Scholar
  31. 31.
    Schweinsburg BC, Taylor MJ, Alhassoon OM, et al. Brain mitochondrial injury in human immunodeficiency virus—seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol. 2005;11:356–64.PubMedGoogle Scholar
  32. 32.
    Bozzette SA, Santangelo J, Villasana D, et al. Peripheral nerve function in persons with asymptomatic or minimally symptomatic HIV disease: absence of zidovudine neurotoxicity. J Acquir Immune Defic Syndr. 1991;4:851–5.PubMedGoogle Scholar
  33. 33.
    Scruggs ER, Dirks Naylor AJ. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology. 2008;82:83–8.PubMedGoogle Scholar
  34. 34.
    Chariot P, Drogou I, de Lacroix-Szmania I, et al. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol. 1999;30:156–60.PubMedGoogle Scholar
  35. 35.
    Cote HC, Brumme ZL, Craib KJ, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med. 2002;346:811–20.PubMedGoogle Scholar
  36. 36.
    Mussini C, Pinti M, Bugarini R, et al. Effect of treatment interruption monitored by CD4 cell count on mitochondrial DNA content in HIV-infected patients: a prospective study. AIDS. 2005;19:1627–33.PubMedGoogle Scholar
  37. 37.
    Montaner JS, Cote HC, Harris M, et al. Mitochondrial toxicity in the era of HAART: evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy. J Acquir Immune Defic Syndr. 2003;34:S85–90.PubMedGoogle Scholar
  38. 38.
    Chiappini F, Teicher E, Saffroy R, et al. Prospective evaluation of blood concentration of mitochondrial DNA as a marker of toxicity in 157 consecutively recruited untreated or HAART-treated HIV-positive patients. Lab Invest. 2004;84:908–14.PubMedGoogle Scholar
  39. 39.
    Gerschenson M, Shiramizu B, LiButti DE, et al. Mitochondrial DNA levels of peripheral blood mononuclear cells and subcutaneous adipose tissue from thigh, fat and abdomen of HIV-1 seropositive and negative individuals. Antivir Ther. 2005;10:M83–9.PubMedGoogle Scholar
  40. 40.
    Chariot P, Monnet I, Gherardi R. Cytochrome c oxidase reaction improves histopathological assessment of zidovudine myopathy. Ann Neurol. 1993;34:561–5.PubMedGoogle Scholar
  41. 41.
    Peters BS, Winer J, Landon DN, et al. Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Q J Med. 1993;86:5–15.PubMedGoogle Scholar
  42. 42.
    Mhiri C, Baudrimont M, Bonne G, et al. Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol. 1991;29:606–14.PubMedGoogle Scholar
  43. 43.
    Arnaudo E, Dalakas M, Shanske S, et al. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet. 1991;337:508–10.PubMedGoogle Scholar
  44. 44.
    Dalakas MC, Illa I, Pezeshkpour GH, et al. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med. 1990;322:1098–105.PubMedGoogle Scholar
  45. 45.
    Simpson DM, Citak KA, Godfrey E, et al. Myopathies associated with human immunodeficiency virus and zidovudine: can their effects be distinguished? Neurology. 1993;43:971–6.PubMedGoogle Scholar
  46. 46.
    Chariot P, Monnet I, Mouchet M, et al. Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy. Arthritis Rheum. 1994;37:583–6.PubMedGoogle Scholar
  47. 47.
    ter Hofstede HJ, Willems HL, Koopmans PP. Serum l-lactate and pyruvate in HIV-infected patients with and without presumed NRTI-related adverse events compared to healthy volunteers. J Clin Virol. 2004;29:44–50.PubMedGoogle Scholar
  48. 48.
    Barret B, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS. 2003;17:1769–85.PubMedGoogle Scholar
  49. 49.
    Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet. 1999;354:1084–9.PubMedGoogle Scholar
  50. 50.
    Tovo PA, Chiapello N, Gabiano C, et al. Zidovudine administration during pregnancy and mitochondrial disease in the offspring. Antivir Ther. 2005;10:697–9.PubMedGoogle Scholar
  51. 51.
    Tardieu M, Brunelle F, Raybaud C, et al. Cerebral MR imaging in uninfected children born to HIV-seropositive mothers and perinatally exposed to zidovudine. AJNR Am J Neuroradiol. 2005;26:695–701.PubMedGoogle Scholar
  52. 52.
    Poirier MC, Divi RL, Al-Harthi L, et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J Acquir Immune Defic Syndr. 2003;33:175–83.PubMedGoogle Scholar
  53. 53.
    Culnane M, Fowler MG, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. JAMA. 1999;281:151–7.PubMedGoogle Scholar
  54. 54.
    Lindegren ML, Rhodes P, Gordon L, et al. Drug safety during pregnancy and in infants: lack of mortality related to mitochondrial dysfunction among perinatally HIV-exposed children in pediatric HIV surveillance. Ann N Y Acad Sci. 2000;918:222–35.PubMedGoogle Scholar
  55. 55.
    Siegfried N, van der Merwe L, Brocklehurst P, Sint TT. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev. 2011;7:CD003510.PubMedGoogle Scholar
  56. 56.
    Pfeffer G, Cote HC, Montaner JS, et al. Ophthalmoplegia and ptosis: mitochondrial toxicity in patients receiving HIV therapy. Neurology. 2009;73:71–2.PubMedGoogle Scholar
  57. 57.
    Landreau-Mascaro A, Barret B, Mayaux MJ, et al. Risk of early febrile seizure with perinatal exposure to nucleoside analogues. Lancet. 2002;359:583–4.PubMedGoogle Scholar
  58. 58.
    Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med. 1987;317:192–7.PubMedGoogle Scholar
  59. 59.
    Hagler DN, Frame PT. Azidothymidine neurotoxicity. Lancet. 1986;2:1392–3.PubMedGoogle Scholar
  60. 60.
    D’Silva M, Leibowitz D, Flaherty JP. Seizure associated with zidovudine. Lancet. 1995;346:452.PubMedGoogle Scholar
  61. 61.
    Routy JP, Prajs E, Blanc AP, et al. Seizure after zidovudine overdose. Lancet. 1989;1:384–5.PubMedGoogle Scholar
  62. 62.
    Pascual-Sedano B, Iranzo A, Marti-Fàbregas J, et al. Prospective study of new-onset seizures in patients with human immunodeficiency virus infection: etiologic and clinical aspects. Arch Neurol. 1999;56:609–12.PubMedGoogle Scholar
  63. 63.
    Saracchini S, Vaccher E, Covezzi E, et al. Lethal neurotoxicity associated to azidothymidine therapy. J Neurol Neurosurg Psychiatry. 1989;52:544–5.PubMedGoogle Scholar
  64. 64.
    Riedel RR, Clarenbach P, Reetz KP. Coma during azidothymidine therapy for AIDS. J Neurol. 1989;236:185.PubMedGoogle Scholar
  65. 65.
    Schaerf FW, Miller R, Pearlson GD. Manic syndrome associated with zidovudine. JAMA. 1988;30(260):3587–8.Google Scholar
  66. 66.
    Maxwell S, Scheftner WA, Kessler HA, Busch K. Manic syndrome associated with zidovudine treatment. JAMA. 1988;259:3406–7.PubMedGoogle Scholar
  67. 67.
    O’Dowd MA, McKegney FP. Manic syndrome associated with zidovudine. JAMA. 1988;260:3587.Google Scholar
  68. 68.
    Wright JM, Sachdev PS, Perkins RJ, Rodriguez P. Zidovudine-related mania. Med J Aust. 1989;150:339–41.PubMedGoogle Scholar
  69. 69.
    Cespedes MS, Aberg JA. Neuropsychiatric complications of antiretroviral therapy. Drug Saf. 2006;29:865–74.PubMedGoogle Scholar
  70. 70.
    Jay C, Ropka M, Dalakas MC. The drugs 2′,3′-dideoxyinosine (didanosine) and 2′,3′-dideoxycytidine (dideoxycytidine) are safe alternatives in people with AIDS with zidovudine-induced myopathy. J Acquir Immune Defic Syndr. 1994;7:630–1.PubMedGoogle Scholar
  71. 71.
    Schindzielorz A, Pike I, Daniels M, et al. Rates and risk factors for adverse events associated with didanosine in the expanded access program. Clin Infect Dis. 1994;19:1076–83.PubMedGoogle Scholar
  72. 72.
    Butler KM, Husson RN, Balis FM, et al. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engl J Med. 1991;324:137–44.PubMedGoogle Scholar
  73. 73.
    Videx [package insert]. Princeton: Bristol-Myers Squibb; 2012.Google Scholar
  74. 74.
    Whitcup SM, Dastgheib K, Nussenblatt RB, et al. A clinicopathologic report of the retinal lesions associated with didanosine. Arch Ophthalmol. 1994;112:1594–8.PubMedGoogle Scholar
  75. 75.
    Whitcup SM, Butler KM, Pizzo PA, Nussenblatt RB. Retinal lesions in children treated with dideoxyinosine. N Engl J Med. 1992;326:1226–7.PubMedGoogle Scholar
  76. 76.
    Cobo J, Ruiz MF, Figueroa MS, et al. Retinal toxicity associated with didanosine in HIV-infected adults. AIDS. 1996;10:1297–300.PubMedGoogle Scholar
  77. 77.
    Fernando AI, Anderson OA, Holder GE, Mitchell SM. Didanosine-induced retinopathy in adults can be reversible. Eye (Lond). 2006;20:1435–7.Google Scholar
  78. 78.
    Brouillette MJ, Chouinard G, Lalonde R. Didanosine-induced mania in HIV infection. Am J Psychiatry. 1994;151:1839–40.PubMedGoogle Scholar
  79. 79.
    McGrath CJ, Njoroge J, John-Stewart GC, et al. Increased incidence of symptomatic peripheral neuropathy among adults receiving stavudine- versus zidovudine-based antiretroviral regimens in Kenya. J Neurovirol. 2012;18:200–4.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Sacktor N, Nakasujja N, Skolasky RL, et al. Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda. Neurology. 2009;72:165–70.PubMedGoogle Scholar
  81. 81.
    Gottlieb M, Peterson D, Adler M. Comparison of safety and efficacy of 2 doses of stavudine (Zerit, stavudine) in a large simple trial in the US parallel track program [abstract no. I171]. 35th ICAAC, San Francisco, p. 235 (1995).Google Scholar
  82. 82.
    Pujades-Rodríguez M, Dantony E, Pinoges L, et al. Toxicity associated with stavudine dose reduction from 40 to 30 mg in first-line antiretroviral therapy. PLoS ONE. 2011;6:e28112.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Harrison TB, Smith B. Neuromuscular manifestations of HIV/AIDS. J Clin Neuromuscul Dis. 2011;13:68–84.PubMedGoogle Scholar
  84. 84.
    Shah SS, Rodriguez T, McGowan JP. Miller Fisher variant of Guillain–Barré syndrome associated with lactic acidosis and stavudine therapy. Clin Infect Dis. 2003;36:e131–3.PubMedGoogle Scholar
  85. 85.
    Simpson D, Estanislao L, Evans S, et al. HIV-associated neuromuscular weakness syndrome. AIDS. 2004;18:1403–12.Google Scholar
  86. 86.
    Capers KN, Turnacioglu S, Leshner RT, Crawford JR. Antiretroviral therapy-associated acute motor and sensory axonal neuropathy. Case Rep Neurol. 2011;3:1–6.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Verma A, Roland M, Jayaweera D, Kett D. Fulminant neuropathy and lactic acidosis associated with nucleoside analog therapy. Neurology. 1999;53:1365–9.PubMedGoogle Scholar
  88. 88.
    Wooltorton E. HIV drug stavudine (Zerit, stavudine) and symptoms mimicking Guillain–Barré syndrome. CMAJ. 2002;166:1067.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Rosso R, Di Biagio A, Ferrazin A, et al. Fatal lactic acidosis and mimicking Guillain–Barré syndrome in an adolescent with human immunodeficiency virus infection. Pediatr Infect Dis J. 2003;22:668–70.PubMedGoogle Scholar
  90. 90.
    Vorasayan P, Phanthumchinda K. Lactic acidosis associated with severe neuromuscular weakness and stavudine therapy. J Med Assoc Thai. 2011;94:501–4.PubMedGoogle Scholar
  91. 91.
    White AJ. Mitochondrial toxicity and HIV therapy. Sex Transm Infect. 2001;77:158–73.PubMedGoogle Scholar
  92. 92.
    Fodale V, Mazzeo A, Pratico C, et al. Fatal exacerbation of peripheral neuropathy during lamivudine therapy: evidence for iatrogenic mitochondrial damage. Anaesthesia. 2005;60:806–10.PubMedGoogle Scholar
  93. 93.
    Cupler EJ, Dalakas MC. Exacerbation of peripheral neuropathy by lamivudine. Lancet. 1995;345:460–1.PubMedGoogle Scholar
  94. 94.
    Song X, Hu Z, Zhang H. Acute dystonia induced by lamivudine. Clin Neuropharmacol. 2005;28:193–4.PubMedGoogle Scholar
  95. 95.
    Nuray A, Yucel U, Numan K, et al. Acute dystonia during pegylated interferon alpha therapy in a case with chronic hepatitis B infection. Clin Neuropharmacol. 2004;27:105–7.Google Scholar
  96. 96.
    Pollock K, Stebbing J, Bower M, et al. Emtricitabine intolerance in treatment-experienced patients switched from lamivudine: a method of assessing toxicity. J Antimicrob Chemother. 2006;58:227–8.PubMedGoogle Scholar
  97. 97.
    Palacios R, Terrón A, Hidalgo A, et al. Minor emtricitabine intolerance in treatment-stable patients switched from tenofovir/lamivudine to a fixed-dose combination of tenofovir/emtricitabine (Truvada). J Antimicrob Chemother. 2008;61:462–3.PubMedGoogle Scholar
  98. 98.
    Soler Palacin P, Aramburo A, Moraga FA, et al. Neuropsychiatric reaction induced by abacavir in a pediatric human immunodeficiency virus-infected patient. Pediatr Infect Dis J. 2006;25:382.PubMedGoogle Scholar
  99. 99.
    Colebunders R, Hilbrands R, De Roo A, Pelgrom J. Neuropsychiatric reaction induced by abacavir. Am J Med. 2002;113:616.PubMedGoogle Scholar
  100. 100.
    Brouilette MJ, Routy JP. Abacavir sulfate and mania in HIV. Am J Psychiatry. 2007;164:979–80.PubMedGoogle Scholar
  101. 101.
    Foster R, Olajide D, Everall IP. Antiretroviral therapy-induced psychosis: case report and brief review of the literature. HIV Med. 2003;4:139–44.PubMedGoogle Scholar
  102. 102.
    Foster R, Taylor C, Everall IP. More on abacavir-induced neuropsychiatric reactions. AIDS. 2004;18:2449.PubMedGoogle Scholar
  103. 103.
    Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371:1417–26.PubMedGoogle Scholar
  104. 104.
    Strategies for Management of Anti-Retroviral Therapy/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17–24.Google Scholar
  105. 105.
    Bedimo RJ, Westfall AO, Drechsler H, et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis. 2011;53:84–91.PubMedGoogle Scholar
  106. 106.
    Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr. 2012;61:441–7.PubMedGoogle Scholar
  107. 107.
    Allavena C, Le Moal G, Michau C, et al. Neuropsychiatric adverse events after switching from an antiretroviral regimen containing efavirenz without tenofovir to an efavirenz regimen containing tenofovir: a report of nine cases. Antivir Ther. 2006;11:263–5.PubMedGoogle Scholar
  108. 108.
    Rotger M, Colombo S, Furrer H, et al. Does tenofovir influence efavirenz pharmacokinetics? Antivir Ther. 2007;12:115–8.PubMedGoogle Scholar
  109. 109.
    Wise ME, Mistry K, Reid S. Drug points: neuropsychiatric complications of nevirapine treatment. BMJ. 2002;324:879.PubMedGoogle Scholar
  110. 110.
    Morlese JF, Qazi NA, Gazzard BG, Nelson MR. Nevirapine-induced neuropsychiatric complications, a class effect of non-nucleoside reverse transcriptase inhibitors? AIDS. 2002;16:1840–1.PubMedGoogle Scholar
  111. 111.
    Pollard RB, Robinson P, Dransfield K. Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection. Clin Ther. 1998;20:1071–92.PubMedGoogle Scholar
  112. 112.
    Sutterlin S, Vogele C, Gauggel S. Neuropsychiatric complications of efavirenz therapy: suggestions for a new research paradigm. J Neuropsychiatry Clin Neurosci. 2010;22:361–9.PubMedGoogle Scholar
  113. 113.
    Fumaz CR, Tuldra A, Ferrer MJ, et al. Quality of life, emotional status and adherence in patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquir Immune Defic Syndr. 2002;29:244–53.PubMedGoogle Scholar
  114. 114.
    Clifford DB, Evans S, Yang Y, et al. Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials. 2009;10:343–55.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Ciccarelli N, Fabbiani M, Di Giambenedetto S, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology. 2011;7(6):1403–9.Google Scholar
  116. 116.
    Clifford DB, Evans S, Yang Y, et al. Impact of efavrienz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005;143:714–21.PubMedGoogle Scholar
  117. 117.
    Hawkins T, Geist C, Young B, et al. Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients. HIV Clin Trials. 2005;6:187–96.PubMedGoogle Scholar
  118. 118.
    Blanch J, Martinez E, Rousaud A, et al. Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz. J Acquir Immune Defic Syndr. 2001;27:336–43.PubMedGoogle Scholar
  119. 119.
    Fumaz CR, Munoz-Moreno JA, Molto J, et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr. 2005;38:560–5.PubMedGoogle Scholar
  120. 120.
    Perez-Molina JA. Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. HIV Clin Trials. 2002;3:279–86.PubMedGoogle Scholar
  121. 121.
    Boly L, Cafaro V, Dyner T. Depressive symptoms predict increased incidence of neuropsychiatric side effects in patients treated with efavirenz. J Acquir Immune Defic Syndr. 2006;42:514–5.PubMedGoogle Scholar
  122. 122.
    Spire B, Carrieri P, Garzot MA. Factors associated with efavirenz discontinuation in a large community-based sample of patients. AIDS Care. 2004;16:558–64.PubMedGoogle Scholar
  123. 123.
    Raines C, Radcliffe O, Treisman GJ. Neurologic and psychiatric complications of antiretroviral agents. J Assoc Nurses AIDS Care. 2005;16:35–48.PubMedGoogle Scholar
  124. 124.
    Quereda C, Corral I, Moreno A, et al. Effect of treatment with efavirenz on neuropsychiatric adverse events of interferon in HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr. 2008;49:61–3.PubMedGoogle Scholar
  125. 125.
    Bickel M, Stephan C, Rottmann C, et al. Severe CNS side-effect and persistent high efavirenz plasma levels in a patient with HIV/ HCV coinfection and liver cirrhosis. Scand J Infect Dis. 2005;37:520–2.PubMedGoogle Scholar
  126. 126.
    O’Mahony S, Myint A, Steinbusch H, et al. Efavirenz induces depressive- like behavior, increased stress response and changes in the immune response in rats. Neuroimmunomodulation. 2005;12:293–8.PubMedGoogle Scholar
  127. 127.
    Streck EL, Scaini G, Rezin GT, et al. Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity. Metab Brain Dis. 2008;23:485–92.PubMedGoogle Scholar
  128. 128.
    Streck EL, Ferreira GK, Scaini G, et al. Non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine inhibit cytochrome C oxidase in mouse brain regions. Neurochem Res. 2011;36:962–6.PubMedGoogle Scholar
  129. 129.
    Tovar-y-Romo LB, Bumpus NN, Pomerantz D, et al. Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J Pharmacol Exp Ther. 2012;343:696–703.PubMedGoogle Scholar
  130. 130.
    Best BM, Koopmans PP, Letendre SL, et al. Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J Antimicrob Chemother. 2011;66:354–7.PubMedGoogle Scholar
  131. 131.
    Langmann P, Weissbrich B, Desch S, et al. Efavirenz plasma levels for the prediction of treatment failure in heavily pretreated HIV-1 infected patients. Eur J Med Res. 2002;7:309–14.PubMedGoogle Scholar
  132. 132.
    Csajka C, Marzolini C, Fattinger K, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther. 2003;73:20–30.PubMedGoogle Scholar
  133. 133.
    Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15:1192–4.Google Scholar
  134. 134.
    Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. 2005;41:1648–53.PubMedGoogle Scholar
  135. 135.
    Hasse B, Gunthard H, Bleiber G, Krause M. Efavirenz intoxication due to slow hepatic metabolism. Clin Infect Dis. 2005;40:e22–3.PubMedGoogle Scholar
  136. 136.
    Takahashi M, Ibe S, Kudaka Y, et al. No observable correlation between central nervous system side effects and EFV plasma concentrations in Japanese HIV type 1-infected patients treated with EFV containing HAART. AIDS Res Hum Retroviruses. 2007;23:983–7.PubMedGoogle Scholar
  137. 137.
    van Luin M, Brouwer AM, van der Ven A, et al. Efavirenz dose reduction to 200 mg once daily in a patient treated with rifampicin. AIDS. 2009;23:742–4.PubMedGoogle Scholar
  138. 138.
    Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther. 2005;10:489–98.PubMedGoogle Scholar
  139. 139.
    Ward B, Gorski J, Jones D, et al. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003;306:287–300.PubMedGoogle Scholar
  140. 140.
    Ribaudo HJ, Haas DW, Tierney C, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group study. Clin Infect Dis. 2006;42:401–7.PubMedGoogle Scholar
  141. 141.
    Klein K, Lang T, Saussele T, et al. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy efavirenz. Pharmacogenet Genomics. 2005;15:861–79.PubMedGoogle Scholar
  142. 142.
    Gross R, Aplenc R, Tenhave T, et al. Slow efavirenz metabolism genotype is common in Botswana. J Acquir Immune Defic Syndr. 2008;49:336–7.PubMedGoogle Scholar
  143. 143.
    Haas DW, Smeaton LM, Shafer RW, et al. Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical Trials Group study. J Infect Dis. 2005;192:1931–42.PubMedGoogle Scholar
  144. 144.
    King J, Aberg JA. Clinical impact of patient population differences and genomic variation in efavirenz therapy. AIDS. 2008;22:1709–17.PubMedGoogle Scholar
  145. 145.
    Mehlotra RK, Ziats MN, Bockarie MJ, Zimmerman PA. Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea. Eur J Clin Pharmacol. 2006;62:267–75.PubMedGoogle Scholar
  146. 146.
    Lang T, Klein K, Richter T, et al. Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther. 2004;311:34–43.PubMedGoogle Scholar
  147. 147.
    Lindfelt T, O’Brien J, Song JC, et al. Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms. Ann Pharmacother. 2010;44:1572–8.PubMedGoogle Scholar
  148. 148.
    Xu BY, Guo LP, Lee SS, et al. Genetic variability of CYP2B6 polymorphisms in four southern Chinese populations. World J Gastroenterol. 2007;13:2100–3.PubMedGoogle Scholar
  149. 149.
    Gatanaga H, Hayashida T, Tsuchiya K. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis. 2007;45:1230–7.PubMedGoogle Scholar
  150. 150.
    Lubomirov R, Colombo S, di Iulio J, et al. Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J Infect Dis. 2011;203:246–57.PubMedGoogle Scholar
  151. 151.
    Gutierrez-Valencia A, Viciana P, Palacios R, et al. Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events: a randomized trial. Ann Intern Med. 2009;151:149–56.PubMedGoogle Scholar
  152. 152.
    van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr. 2009;52:240–5.PubMedGoogle Scholar
  153. 153.
    Fayet Mello A, Buclin T, Decosterd LA, et al. Successful efavirenz dose reduction guided by therapeutic drug monitoring. Antivir Ther. 2011;16:189–97.PubMedGoogle Scholar
  154. 154.
    Cabrera Figueroa S, Iglesias Gómez A, et al. Long-term efficacy and safety of efavirenz dose reduction to 200 mg once daily in a Caucasian patient with HIV. Clin Drug Investig. 2010;30:405–11.PubMedGoogle Scholar
  155. 155.
    Waters L, Fisher M, Winston A, et al. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS. 2011;25:65–71.PubMedGoogle Scholar
  156. 156.
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Section accessed [June 17, 2012]. Updated September 14, 2011. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
  157. 157.
    Fundaro C, Genovese O, Rendeli C, et al. Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS. 2002;16:299–300.Google Scholar
  158. 158.
    Watts DH. Teratogenicity risk of antiretroviral therapy in pregnancy. Curr HIV/AIDS Rep. 2007;4:135–40.PubMedGoogle Scholar
  159. 159.
    De Santis M, Carducci B, De Santis L, et al. Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med. 2002;162:355.PubMedGoogle Scholar
  160. 160.
    Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2011;25:2301–4.PubMedGoogle Scholar
  161. 161.
    Saitoh A, Hull AD, Franklin P, Spector SA. Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. 2005;25:555–6.PubMedGoogle Scholar
  162. 162.
    Gallego L, Barreiro P, del Rio R, et al. Analyzing sleep abnormalities in HIV-infected patients treated with efavirenz. Clin Infect Dis. 2004;38:430–2.PubMedGoogle Scholar
  163. 163.
    Blank A, Hellstern V, Schuster D, et al. Efavirenz treatment and false-positive results in benzodiazepine screening tests. Clin Infect Dis. 2009;48:1787–9.PubMedGoogle Scholar
  164. 164.
    Damsa C, Bandelier C, Maris S, et al. Recurrence of post-traumatic stress disorder and antiretrovirals. Scand J Infect Dis. 2005;37:313–6.PubMedGoogle Scholar
  165. 165.
    Moreno A, Labelle C, Samet JH. Recurrence of post-traumatic stress disorder symptoms after initiation of antiretrovirals including efavirenz: a report of two cases. HIV Med. 2003;4:302–4.PubMedGoogle Scholar
  166. 166.
    Sustiva [package insert]. Wilmington: DuPont Pharmaceuticals; 2012.Google Scholar
  167. 167.
    Nelson M, Stellbrink HJ, Podzamczer D, et al. A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. AIDS. 2011;25:335–40.PubMedGoogle Scholar
  168. 168.
    Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378:238–46.PubMedGoogle Scholar
  169. 169.
    Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53:4–9.PubMedGoogle Scholar
  170. 170.
    Pettersen J, Jones G, Worthington C, et al. Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol. 2006;59:816–24.PubMedGoogle Scholar
  171. 171.
    Smyth K, Affandi J, McArthur J, et al. Prevalence and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993–2006. HIV Med. 2007;8:367–73.PubMedGoogle Scholar
  172. 172.
    Ellis RJ, Marquie-Beck J, Delaney P, et al. Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol. 2008;64:566–72.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Evans SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011;25:919–28.PubMedCentralPubMedGoogle Scholar
  174. 174.
    Bonfanti P, Valsecchi L, Parazzini F, et al. Incidence of adverse reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio Allergia e Infezione da HIV (CISAI) Group. J Acquir Immune Defic Syndr. 2000;23:236–45.PubMedGoogle Scholar
  175. 175.
    Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet. 1998;351:543–9.PubMedGoogle Scholar
  176. 176.
    Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med. 1995;333:1534–9.PubMedGoogle Scholar
  177. 177.
    Gatti G, Di Biagio A, Casazza R, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS. 1999;13:2083–9.PubMedGoogle Scholar
  178. 178.
    Gupta S, Knight AG, Losso BY, et al. Brain injury caused by HIV protease inhibitors: role of lipodystrophy and insulin resistance. Antiviral Res. 2012;95:19–29.PubMedCentralPubMedGoogle Scholar
  179. 179.
    Justice AC, Zingmond DS, Gordon KS, et al. Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage? Clin Infect Dis. 2008;47:1226–30.PubMedGoogle Scholar
  180. 180.
    Schiffman SS, Zervakis J, Heffron S, Heald AE. Effect of protease inhibitors on the sense of taste. Nutrition. 1999;15:767–72.PubMedGoogle Scholar
  181. 181.
    Murri R, Ammassari A, Gallicano K, et al. Patient-reported nonadherence to HAART is related to protease inhibitor levels. J Acquir Immune Defic Syndr. 2000;24:123–8.PubMedGoogle Scholar
  182. 182.
    Melvin AJ, Mohan KM, Arcuino LA, et al. Clinical, virologic and immunologic responses of children with advanced human immunodeficiency virus type 1 disease treated with protease inhibitors. Pediatr Infect Dis J. 1997;16:968.PubMedGoogle Scholar
  183. 183.
    Roe RH, Jumper JM, Gualino V, et al. Retinal pigment epitheliopathy, macular telangiectasis, and intraretinal crystal deposits in HIV-positive patients receiving ritonavir. Retina. 2011;31:559–65.PubMedGoogle Scholar
  184. 184.
    Huitema AD, Kuiper RA, Meenhorst PL, et al. Photophobia in a patient with high indinavir plasma concentrations. Ther Drug Monit. 2003;25:735–7.PubMedGoogle Scholar
  185. 185.
    Gariano RF, Cooney EL. Uveitits following administration of the protease inhibitor indinavir to a patient with AIDS. Clin Infect Dis. 1997;24:529.PubMedGoogle Scholar
  186. 186.
    Akler ME, Johnson DW, Burman WJ, Johnson SC. Anterior uveitis and hypotony after intravenous cidofovir for the treatment of cytomegalovirus retinitis. Ophthalmology. 1998;105:651–7.PubMedGoogle Scholar
  187. 187.
    Williams B. Ototoxicity may be associated with protease inhibitor therapy. Clin Infect Dis. 2001;33:2100–2.PubMedGoogle Scholar
  188. 188.
    James CW, McNelis KC, Matalia MD, et al. Central nervous system toxicity and amprenavir oral solution. Ann Pharmacother. 2002;36:174.PubMedGoogle Scholar
  189. 189.
    Perez-Valero I, Bayon C, Cambron I, et al. Protease inhibitor monotherapy and the CNS: peace of mind? J Antimicrob Chemother. 2011;66:1954–62.PubMedGoogle Scholar
  190. 190.
    Ovbiagele B, Nath A. Increasing incidence of ischemic stroke in patients with HIV infection. Neurology. 2011;76:444–50.PubMedGoogle Scholar
  191. 191.
    Friis-Moller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients—association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179–93.PubMedGoogle Scholar
  192. 192.
    Goodkin K, Wilkie FL, Concha M, et al. Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality. J Clin Epidemiol. 2001;54:S35–43.PubMedGoogle Scholar
  193. 193.
    Jerico C, Knobel H, Calvo N, et al. Subclinical carotid atherosclerosis in HIV-infected patients: role of combination antiretroviral therapy. Stroke. 2006;37:812–7.PubMedGoogle Scholar
  194. 194.
    Rasmussen LD, Engsig FN, Christensen H, et al. Risk of cerebrovascular events in persons with and without HIV: a Danish nationwide population-based cohort study. AIDS. 2011;25:1637–46.PubMedGoogle Scholar
  195. 195.
    Cherry CL, Duncan AJ, Mackie KF, et al. A report on the effect of commencing enfuvirtide on peripheral neuropathy. AIDS Res Hum Retroviruses. 2008;24:1027–30.PubMedGoogle Scholar
  196. 196.
    Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003;348:2186–95.PubMedGoogle Scholar
  197. 197.
    Fung HB, Guo Y. Enfuvirtide: a fusion inhibitor for the treatment of HIV infection. Clin Ther. 2004;26:352–78.PubMedGoogle Scholar
  198. 198.
    Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. AIDS. 2008;22:1890–2.PubMedGoogle Scholar
  199. 199.
    Eiden C, Peyriere H, Peytavin G, Reynes J. Severe insomnia related to high concentrations of raltegravir. AIDS. 2011;25:725–7.PubMedGoogle Scholar
  200. 200.
    Teppler H, Brown DD, Leavitt RY, et al. Long-term safety from the raltegravir clinical development program. Curr HIV Res. 2011;9:40–53.PubMedCentralPubMedGoogle Scholar
  201. 201.
    Lee FJ, Amin J, Bloch M, et al. Skeletal muscle toxicity associated with raltegravir-based combination antiretroviral therapy in HIV-infected adults. J Acquir Immune Defic Syndr. 2013;62:525–33.PubMedGoogle Scholar
  202. 202.
    Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011;6:F7–12.Google Scholar
  203. 203.
    Selzentry [package insert]. New York: Pfizer Inc; 2012.Google Scholar
  204. 204.
    Lim JK, McDermott DH, Lisco A. CCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission. J Infect Dis. 2010;201:178–85.PubMedCentralPubMedGoogle Scholar
  205. 205.
    Arenas-Pinto A, Bhaskaran K, Dunn D, Weller IV. The risk of developing peripheral neuropathy induced by nucleoside reverse transcriptase inhibitors decreases over time: evidence from the Delta trial. Antivir Ther. 2008;13:289–95.PubMedGoogle Scholar
  206. 206.
    Childs EA, Lyles RH, Selnes OA, et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology. 1999;52:607–13.PubMedGoogle Scholar
  207. 207.
    Cherry CL, Affandi JS, Imran D, et al. Age and height predict neuropathy risk in patients with HIV prescribed stavudine. Neurology. 2009;73:315–20.PubMedGoogle Scholar
  208. 208.
    Phan V, Thai S, Choun K, et al. Incidence of treatment-limiting toxicity with stavudine-based antiretroviral therapy in cambodia: a retrospective cohort study. PLoS ONE. 2012;7:e30647.PubMedCentralPubMedGoogle Scholar
  209. 209.
    Hulgan T, Haas DW, Haines JL, et al. Mitochondrial haplogroups and peripheral neuropathy during antiretrovirals therapy: an Adult AIDS Clinical Trials Group study. AIDS. 2005;19:1341–9.PubMedGoogle Scholar
  210. 210.
    Canter JA, Robbins GK, Selph D, et al. African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy. J Infect Dis. 2010;201:1703–7.PubMedCentralPubMedGoogle Scholar
  211. 211.
    Yamanaka H, Gatanaga H, Kosalaraksa P, 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.PubMedGoogle Scholar
  212. 212.
    Cherry CL, Rosenow A, Affandi JS, et al. Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual’s NRTI-SN risk. AIDS Res Hum Retroviruses. 2008;24:117–23.PubMedGoogle Scholar
  213. 213.
    Affandi JS, Price P, Imran D, et al. Can we predict neuropathy risk before stavudine prescription in a resource-limited setting? AIDS Res Hum Retroviruses. 2008;24:1281–4.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Michael S. Abers
    • 1
  • Wayne X. Shandera
    • 1
  • Joseph S. Kass
    • 1
  1. 1.Baylor College of MedicineHoustonUSA

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