Drug Safety

, Volume 39, Issue 10, pp 945–957 | Cite as

Neuropsychiatric Effects of HIV Antiviral Medications

  • Glenn J. Treisman
  • Olivia Soudry
Review Article


The development of antiretroviral therapy (ART) has dramatically increased the lifespan of HIV patients but treatment is complicated by numerous adverse effects and toxicities. ART complications include neuropsychiatric, metabolic, gastrointestinal, cardiac, and numerous other toxicities, and clinicians often have to choose one toxicity over another to offer the best medication regimen for a patient. Some antiviral drugs cause significant neuropsychiatric complications, including depression, cognitive impairment, and sleep disturbance. Even in careful studies, it may be difficult to determine which effects are related to the virus, the immune system, or the treatment. Of the six currently marketed classes of antiviral drugs, the nucleoside reverse transcriptase inhibitors and the non-nucleoside reverse transcriptase inhibitors have been most commonly associated with neuropsychiatric complications. Within these classes, certain drugs are more likely to cause difficulty than others. We review the contention regarding the central nervous system (CNS) complications of efavirenz, as well as debate about the role of CNS penetration in drug effectiveness and toxicity. A thorough working knowledge of the neuropsychiatric consequences of ART allows clinicians to tailor treatment more successfully to individual patients as well as to identify ART more quickly as the source of a problem or symptom.


Efavirenz Nevirapine Darunavir Raltegravir Maraviroc 
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.


Compliance with Ethical Standards


Our clinical work is supported in part by Ryan White funds; however, none of these funds went towards the writing of this paper.

Conflict of interest

Glenn J. Treisman and Olivia Soudry have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Centers for Disease Control (CDC). Pneumocystis pneumonia–Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30(21):250–2.Google Scholar
  2. 2.
    Centers for Disease C. Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men–New York City and California. MMWR Morb Mortal Wkly Rep. 1981;30(25):305–8.Google Scholar
  3. 3.
    Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med. 1981;305(24):1425–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Masur H, Michelis MA, Greene JB, Onorato I, Stouwe RA, Holzman RS, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med. 1981;305(24):1431–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Siegal FP, Lopez C, Hammer GS, Brown AE, Kornfeld SJ, Gold J, et al. Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med. 1981;305(24):1439–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Broder S, Gallo RC. A pathogenic retrovirus (HTLV-III) linked to AIDS. N Engl J Med. 1984;311(20):1292–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, et al. 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci. 1985;82(20):7096–100.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    AIDSinfo. Clinical guideline portal. Accessed.
  9. 9.
    Dabby R, Djaldetti R, Gilad R, Herman O, Frand J, Sadeh M, et al. Acute heroin-related neuropathy. J Peripher Nerv Syst. 2006;11(4):304–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17(1):3–16.PubMedCrossRefGoogle Scholar
  11. 11.
    McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St Clair M, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol. 1997;42(5):689–98.PubMedCrossRefGoogle Scholar
  12. 12.
    Gisslen M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis. 2011;11:356.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Treisman G, Fishman M, Schwartz J, Hutton H, Lyketsos C. Mood disorders in HIV infection. Depress Anxiety. 1998;7(4):178–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Dean B. Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies. Int J Neuropsychopharmacol. 2011;14(7):997–1012.PubMedCrossRefGoogle Scholar
  15. 15.
    Sewell DD, Jeste DV, McAdams LA, Bailey A, Harris MJ, Atkinson JH, et al. Neuroleptic treatment of HIV-associated psychosis. HNRC group. Neuropsychopharmacology. 1994;10(4):223–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Burger DM, Meenhorst PL, Beijnen JH. Concise overview of the clinical pharmacokinetics of dideoxynucleoside antiretroviral agents. Pharm World Sci. 1995;17(2):25–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Aweeka F, Jayewardene A, Staprans S, Bellibas SE, Kearney B, Lizak P, et al. Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1–infected patients with and without AIDS dementia complex. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20(1):39–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, et al. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol. 2004;56(3):416–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. 2011;25(3):357–65.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Lanoy E, Guiguet M, Bentata M, Rouveix E, Dhiver C, Poizot-Martin I, et al. Survival after neuroAIDS: association with antiretroviral CNS penetration-effectiveness score. Neurology. 2011;76(7):644–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Cysique LA, Waters EK, Brew BJ. Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol. 2011;22(11):148.CrossRefGoogle Scholar
  22. 22.
    Vassallo M, Durant J, Biscay V, Lebrun-Frenay C, Dunais B, Laffon M, et al. Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? AIDS. 2014;28(4):493–501.PubMedCrossRefGoogle Scholar
  23. 23.
    Kahouadji Y, Dumurgier J, Sellier P, Lapalus P, Delcey V, Bergmann J, et al. Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score. HIV Med. 2013;14(5):311–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Caniglia EC, Cain LE, Justice A, Tate J, Logan R, Sabin C, HIV-CAUSAL Collaboration, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology. 2014;83(2):134–41.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Berger JR, Clifford DB. The relationship of CPE to HIV dementia: slain by an ugly fact? Neurology. 2014;83(2):109–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Hammond ER, Crum RM, Treisman GJ, Mehta SH, Marra CM, Clifford DB, Morgello S, Simpson DM, Gelman BB, Ellis RJ, Grant I, Letendre SL, McArthur JC, CHARTER Group. The cerebrospinal fluid HIV risk score for assessing central nervous system activity in persons with HIV. Am J Epidemiol. 2014;180(3):297–307.Google Scholar
  27. 27.
    Fabbiani M, Grima P, Milanini B, Mondi A, Baldonero E, Ciccarelli N, et al. Antiretroviral neuropenetration scores better correlate with cognitive performance of HIV-infected patients after accounting for drug susceptibility. Antivir Ther. 2015;20(4):441–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Carvalhal A, Gill MJ, Letendre SL, Rachlis A, Bekele T, Raboud J, Centre for Brain Health in HIV/AIDS, et al. Central nervous system penetration effectiveness of antiretroviral drugs and neuropsychological impairment in the Ontario HIV Treatment Network Cohort Study. J Neurovirol. 2016;22(3):349–57.PubMedCrossRefGoogle Scholar
  29. 29.
    Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998;12(14):1735–44.Google Scholar
  30. 30.
    Keswani SC, Pardo CA, Cherry CL, Hoke A, McArthur JC. HIV-associated sensory neuropathies. AIDS. 2002;16(16):2105–17.PubMedCrossRefGoogle Scholar
  31. 31.
    Hulgan T, Haas DW, Haines JL, Ritchie MD, Robbins GK, Shafer RW, et al. Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS. 2005;19(13):1341–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Canter JA, Robbins GK, Selph D, Clifford DB, Kallianpur AR, Shafer R, et al. African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy. J Infect Dis. 2010;201(11):1703–7.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Yamanaka H, Gatanaga H, Kosalaraksa P, Matsuoka-Aizawa S, Takahashi T, Kimura S, et al. Novel mutation of human DNA polymerase gamma associated with mitochondrial toxicity induced by anti-HIV treatment. J Infect Dis. 2007;195(10):1419–25.PubMedCrossRefGoogle Scholar
  34. 34.
    Cherry CL, Rosenow A, Affandi JS, McArthur JC, Wesselingh SL, Price P. 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 Retrovir. 2008;24(2):117–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Ferrari LF, Levine JD. Alcohol consumption enhances antiretroviral painful peripheral neuropathy by mitochondrial mechanisms. Eur J Neurosci. 2010;32(5):811–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Scruggs ER, Dirks Naylor AJ. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology. 2008;82(2):83–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Maxwell S, Scheftner WA, Kessler HA, Busch K. Manic syndrome associated with zidovudine treatment. JAMA. 1988;259(23):3406–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Wright JM, Sachdev PS, Perkins RJ, Rodriguez P. Zidovudine-related mania. Med J Aust. 1989;150(6):339–41.PubMedGoogle Scholar
  39. 39.
    O’Dowd MA, McKegney FP. Manic syndrome associated with zidovudine. JAMA. 1988;260(24):3587–8.CrossRefGoogle Scholar
  40. 40.
    Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, 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(4):192–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Hagler DN, Frame PT. Azidothymidine neurotoxicity. Lancet. 1986;2(8520):1392–3.PubMedCrossRefGoogle Scholar
  42. 42.
    Routy JP, Prajs E, Blanc AP, Drony S, Moriceau M, Sarrazin C, et al. Seizure after zidovudine overdose. Lancet. 1989;1(8634):384–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Saracchini S, Vaccher E, Covezzi E, Tortorici G, Carbone A, Tirelli U. Lethal neurotoxicity associated to azidothymidine therapy. J Neurol Neurosurg Psychiatry. 1989;52(4):544–5.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    D’Silva M, Leibowitz D, Flaherty JP. Seizure associated with zidovudine. Lancet. 1995;346(8972):452.PubMedCrossRefGoogle Scholar
  45. 45.
    Marra CM, Wechkin HA, Longstreth WT Jr, Rees TS, Syapin CL, Gates GA. Hearing loss and antiretroviral therapy in patients infected with HIV-1. Arch Neurol. 1997;54(4):407–10.PubMedCrossRefGoogle Scholar
  46. 46.
    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(11):1623–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Schouten JT, Lockhart DW, Rees TS, Collier AC, Marra CM. A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naive people. BMC Infect Dis. 2006;6:28.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Khoza-Shangase K. Highly active antiretroviral therapy: does it sound toxic? J Pharm Bioallied Sci. 2011;3(1):142–53.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Whitcup SM, Butler KM, Pizzo PA, Nussenblatt RB. Retinal lesions in children treated with dideoxyinosine. N Engl J Med. 1992;326(18):1226–7.PubMedGoogle Scholar
  50. 50.
    Cobo J, Ruiz MF, Figueroa MS, Antela A, Quereda C, Perez-Elias MJ, et al. Retinal toxicity associated with didanosine in HIV-infected adults. AIDS. 1996;10(11):1297–300.PubMedCrossRefGoogle Scholar
  51. 51.
    Brouillette MJ, Chouinard G, Lalonde R. Didanosine-induced mania in HIV infection. Am J Psychiatry. 1994;151(12):1839–40.PubMedGoogle Scholar
  52. 52.
    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(10):e131–3.PubMedCrossRefGoogle Scholar
  53. 53.
    Group HIVNSS. HIV-associated neuromuscular weakness syndrome. AIDS. 2004;18(10):1403–12.Google Scholar
  54. 54.
    Wooltorton E. HIV drug stavudine (Zerit, d4T) and symptoms mimicking Guillain–Barre syndrome. CMAJ. 2002;166(8):1067.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Rosso R, Di Biagio A, Ferrazin A, Bassetti M, Ciravegna BW, Bassetti D. Fatal lactic acidosis and mimicking Guillain–Barre syndrome in an adolescent with human immunodeficiency virus infection. Pediatr Infect Dis J. 2003;22(7):668–70.PubMedGoogle Scholar
  56. 56.
    Vorasayan P, Phanthumchinda K. Lactic acidosis associated with severe neuromuscular weakness and stavudine therapy. J Med Assoc Thai. 2011;94(4):501–4.PubMedGoogle Scholar
  57. 57.
    Fodale V, Mazzeo A, Pratico C, Aguennouz M, Toscano A, Santamaria LB, et al. Fatal exacerbation of peripheral neuropathy during lamivudine therapy: evidence for iatrogenic mitochondrial damage. Anaesthesia. 2005;60(8):806–10.PubMedCrossRefGoogle Scholar
  58. 58.
    Cupler EJ, Dalakas MC. Exacerbation of peripheral neuropathy by lamivudine. Lancet. 1995;345(8947):460–1.PubMedCrossRefGoogle Scholar
  59. 59.
    Song X, Hu Z, Zhang H. Acute dystonia induced by lamivudine. Clin Neuropharmacol. 2005;28(4):193–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Pollock K, Stebbing J, Bower M, Gazzard B, Nelson M. Emtricitabine intolerance in treatment-experienced patients switched from lamivudine: a method of assessing toxicity. J Antimicrob Chemother. 2006;58(1):227–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Palacios R, Terron A, Hidalgo A, Rivero A, Santos J, SIMVA Group. 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(2):462–3.PubMedCrossRefGoogle Scholar
  62. 62.
    Marcus JL, Neugebauer RS, Leyden WA, Chao CR, Xu L, Quesenberry CP Jr, et al. Use of abacavir and risk of cardiovascular disease among HIV-infected individuals. J Acquir Immune Defic Syndr. 2016;71(4):413–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Brouilette MJ, Routy JP. Abacavir sulfate and mania in HIV. Am J Psychiatry. 2007;164(6):979–80.PubMedCrossRefGoogle Scholar
  64. 64.
    Foster R, Taylor C, Everall IP. More on abacavir-induced neuropsychiatric reactions. AIDS. 2004;18(18):2449.PubMedGoogle Scholar
  65. 65.
    Allavena C, Le Moal G, Michau C, Chiffoleau A, Raffi F. 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(2):263–5.PubMedGoogle Scholar
  66. 66.
    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(6):1071–92.PubMedCrossRefGoogle Scholar
  67. 67.
    Wise ME, Mistry K, Reid S. Drug points: Neuropsychiatric complications of nevirapine treatment. BMJ. 2002;324(7342):879.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Morlese JF, Qazi NA, Gazzard BG, Nelson MR. Nevirapine-induced neuropsychiatric complications, a class effect of non-nucleoside reverse transcriptase inhibitors? AIDS. 2002;16(13):1840–1.PubMedCrossRefGoogle Scholar
  69. 69.
    Apostolova N, Funes HA, Blas-Garcia A, Galindo MJ, Alvarez A, Esplugues JV. Efavirenz and the CNS: what we already know and questions that need to be answered. J Antimicrob Chemother. 2015;70(10):2693–708.PubMedCrossRefGoogle Scholar
  70. 70.
    Sutterlin S, Vogele C, Gauggel S. Neuropsychiatric complications of efavirenz therapy: suggestions for a new research paradigm. J Neuropsychiatry Clin Neurosci. 2010;22(4):361–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Fumaz CR, Tuldra A, Ferrer MJ, Paredes R, Bonjoch A, Jou T, et al. Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquir Immune Defic Syndr. 2002;29(3):244–53.PubMedCrossRefGoogle Scholar
  72. 72.
    Blanch J, Martinez E, Rousaud A, Blanco JL, Garcia-Viejo MA, Peri JM, et al. Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz. J Acquir Immune Defic Syndr. 2001;27(4):336–43.PubMedCrossRefGoogle Scholar
  73. 73.
    Hawkins T, Geist C, Young B, Giblin A, Mercier RC, Thornton K, et al. Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients. HIV Clin Trials. 2005;6(4):187–96.PubMedCrossRefGoogle Scholar
  74. 74.
    Fumaz CR, Munoz-Moreno JA, Molto J, Negredo E, Ferrer MJ, Sirera G, et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr. 2005;38(5):560–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Ciccarelli N, Fabbiani M, Di Giambenedetto S, Fanti I, Baldonero E, Bracciale L, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology. 2011;76(16):1403–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Clifford DB, Evans S, Yang Y, Acosta EP, Ribaudo H, Gulick RM, et al. Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials. 2009;10(6):343–55.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Ma Q, Vaida F, Wong J, Sanders CA, Kao YT, Croteau D, et al. Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol. 2016;22(2):170–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Journot V, Chene G, De Castro N, Rancinan C, Cassuto JP, Allard C, et al. Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099. Clin Infect Dis. 2006;42(12):1790–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Ward DJ, Curtin JM. Switch from efavirenz to nevirapine associated with resolution of efavirenz-related neuropsychiatric adverse events and improvement in lipid profiles. AIDS Patient Care STDS. 2006;20(8):542–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Mothapo KM, Schellekens A, van Crevel R, Keuter M, Grintjes-Huisman K, Koopmans P, et al. Improvement of depression and anxiety after discontinuation of long-term efavirenz treatment. CNS Neurol Disord Drug Targets. 2015;14(6):811–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Pedrol E, Llibre JM, Tasias M, Curran A, Guardiola JM, Deig E, et al. Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study. HIV Med. 2015;16(10):628–34.PubMedCrossRefGoogle Scholar
  82. 82.
    Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014;161(1):1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Smith C, Ryom L, Monforte A, Reiss P, Mocroft A, El-Sadr W, et al. Lack of association between use of efavirenz and death from suicide: evidence from the D:A: D study. J Int AIDS Soc. 2014;17(4 Suppl 3):19512.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Nkhoma ET, Coumbis J, Farr AM, Johnston SS, Chu BC, Rosenblatt LC, et al. No evidence of an association between efavirenz exposure and suicidality among HIV patients initiating antiretroviral therapy in a retrospective cohort study of real world data. Medicine (Baltimore). 2016;95(3):e2480.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Blas-Garcia A, Polo M, Alegre F, Funes HA, Martinez E, Apostolova N, et al. Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz. J Antimicrob Chemother. 2014;69(11):2995–3000.PubMedCrossRefGoogle Scholar
  87. 87.
    Brown LA, Jin J, Ferrell D, Sadic E, Obregon D, Smith AJ, et al. Efavirenz promotes beta-secretase expression and increased Abeta1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND). PLoS One. 2014;9(4):e95500.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Funes HA, Apostolova N, Alegre F, Blas-Garcia A, Alvarez A, Marti-Cabrera M, et al. Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side effects of efavirenz. J Infect Dis. 2014;210(9):1385–95.PubMedCrossRefGoogle Scholar
  89. 89.
    Brandmann M, Nehls U, Dringen R. 8-Hydroxy-efavirenz, the primary metabolite of the antiretroviral drug efavirenz, stimulates the glycolytic flux in cultured rat astrocytes. Neurochem Res. 2013;38(12):2524–34.PubMedCrossRefGoogle Scholar
  90. 90.
    Apostolova N, Funes HA, Blas-Garcia A, Alegre F, Polo M, Esplugues JV. Involvement of nitric oxide in the mitochondrial action of efavirenz: a differential effect on neurons and glial cells. J Infect Dis. 2015;211(12):1953–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Hecht M, Harrer T, Buttner M, Schwegler M, Erber S, Fietkau R, et al. Cytotoxic effect of efavirenz is selective against cancer cells and associated with the cannabinoid system. AIDS. 2013;27(13):2031–40.PubMedCrossRefGoogle Scholar
  92. 92.
    Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, Gonzalez-Maeso J, et al. The HIV antiretroviral drug efavirenz has LSD-like properties. Neuropsychopharmacology. 2013;38(12):2373–84.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Dalwadi DA, Kim S, Amdani SM, Chen Z, Huang RQ, Schetz JA. Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz. Pharmacol Res. 2016;110:10–24.PubMedCrossRefGoogle Scholar
  94. 94.
    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(4):514–5.PubMedCrossRefGoogle Scholar
  95. 95.
    O’Mahony SM, Myint AM, Steinbusch H, Leonard BE. Efavirenz induces depressive-like behaviour, increased stress response and changes in the immune response in rats. NeuroImmunoModulation. 2005;12(5):293–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15(1):71–5.PubMedCrossRefGoogle Scholar
  97. 97.
    Langmann P, Weissbrich B, Desch S, Vath T, Schirmer D, Zilly M, et al. Efavirenz plasma levels for the prediction of treatment failure in heavily pretreated HIV-1 infected patients. Eur J Med Res. 2002;7(7):309–14.PubMedGoogle Scholar
  98. 98.
    Bickel M, Stephan C, Rottmann C, Carlebach A, Haberl A, Kurowski M, 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(6–7):520–2.PubMedCrossRefGoogle Scholar
  99. 99.
    Csajka C, Marzolini C, Fattinger K, Decosterd LA, Fellay J, Telenti A, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther. 2003;73(1):20–30.PubMedCrossRefGoogle Scholar
  100. 100.
    Gutierrez F, Navarro A, Padilla S, Anton R, Masia M, Borras J, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. 2005;41(11):1648–53.PubMedCrossRefGoogle Scholar
  101. 101.
    Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G>T polymorphism, increased plasma efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther. 2010;7:32.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, Khoo S, Back D, Orrell C, Clarke A, Losso M, Phanuphak P, Carey D, Cooper DA, Emery S, Puls R. Comprehensive pharmacokinetic, pharmacodynamic and pharmacogenetic evaluation of once-daily efavirenz 400 and 600 mg in treatment-naïve HIV-Infected patients at 96 Weeks: results of the ENCORE1 Study. Clin Pharmacokinet. 2016;55(7):861–73.Google Scholar
  103. 103.
    Waters L, Fisher M, Winston A, Higgs C, Hadley W, Garvey L, 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(1):65–71.PubMedCrossRefGoogle Scholar
  104. 104.
    Pozniak AL, Morales-Ramirez J, Katabira E, Steyn D, Lupo SH, Santoscoy M, et al. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010;24(1):55–65.PubMedCrossRefGoogle Scholar
  105. 105.
    Molina JM, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saag M, 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(9787):238–46.PubMedCrossRefGoogle Scholar
  106. 106.
    Freeman D, Levenson J. Rilpivirine and depression. Psychosomatics. 2015;56(6):711–2.PubMedCrossRefGoogle Scholar
  107. 107.
    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(4):279–86.PubMedCrossRefGoogle Scholar
  108. 108.
    Spire B, Carrieri P, Garzot MA, L’Henaff M, Obadia Y, TRT-5 Group. Factors associated with efavirenz discontinuation in a large community-based sample of patients. AIDS Care. 2004;16(5):558–64.PubMedCrossRefGoogle Scholar
  109. 109.
    Anderson AC. The process of structure-based drug design. Chem Biol. 2003;10(9):787–97.PubMedCrossRefGoogle Scholar
  110. 110.
    Wlodawer A, Vondrasek J. Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu Rev Biophys Biomol Struct. 1998;27:249–84.PubMedCrossRefGoogle Scholar
  111. 111.
    Pettersen JA, Jones G, Worthington C, Krentz HB, Keppler OT, Hoke A, et al. Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol. 2006;59(5):816–24.PubMedCrossRefGoogle Scholar
  112. 112.
    Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB, McArthur JC, et al. Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol. 2008;64(5):566–72.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Schiffman SS, Zervakis J, Heffron S, Heald AE. Effect of protease inhibitors on the sense of taste. Nutrition. 1999;15(10):767–72.PubMedCrossRefGoogle Scholar
  114. 114.
    Huitema AD, Kuiper RA, Meenhorst PL, Mulder JW, Beijnen JH. Photophobia in a patient with high indinavir plasma concentrations. Ther Drug Monit. 2003;25(6):735–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Williams B. Ototoxicity may be associated with protease inhibitor therapy. Clin Infect Dis. 2001;33(12):2100–2.PubMedCrossRefGoogle Scholar
  116. 116.
    Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003;348(22):2186–95.PubMedCrossRefGoogle Scholar
  117. 117.
    Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. AIDS. 2008;22(14):1890–2.PubMedCrossRefGoogle Scholar
  118. 118.
    Lafay-Chebassier C, Chavant F, Favreliere S, Pizzoglio V, Perault-Pochat MC, French Association of Regional Pharmacovigilance Centers. Drug-induced depression: a case/non case study in the French pharmacovigilance database. Therapie. 2015;70(5):425–32.PubMedCrossRefGoogle Scholar
  119. 119.
    Teppler H, Brown DD, Leavitt RY, Sklar P, Wan H, Xu X, et al. Long-term safety from the raltegravir clinical development program. Curr HIV Res. 2011;9(1):40–53.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Eiden C, Peyriere H, Peytavin G, Reynes J. Severe insomnia related to high concentrations of raltegravir. AIDS. 2011;25(5):725–7.PubMedCrossRefGoogle Scholar
  121. 121.
    Curtis L, Nichols G, Stainsby C, Lim J, Aylott A, Wynne B, et al. Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients. HIV Clin Trials. 2014;15(5):199–208.PubMedCrossRefGoogle Scholar
  122. 122.
    Lee M, Eyer F, Felgenhauer N, Klinker HH, Spinner CD. Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient. AIDS Res Ther. 2015;12:18.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Whitcomb JM, Huang W, Fransen S, Limoli K, Toma J, Wrin T, et al. Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrob Agents Chemother. 2007;51(2):566–75.PubMedCrossRefGoogle Scholar
  124. 124.
    Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, International Antiviral Society-USA Panel, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA. 2014;312(4):410–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral ScienceJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of MedicineMeyer 119 Johns Hopkins HospitalBaltimoreUSA

Personalised recommendations