Journal of NeuroVirology

, Volume 22, Issue 2, pp 170–178 | Cite as

Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients

  • Qing Ma
  • Florin Vaida
  • Jenna Wong
  • Chelsea A. Sanders
  • Yu-ting Kao
  • David Croteau
  • David B. Clifford
  • Ann C. Collier
  • Benjamin B. Gelman
  • Christina M. Marra
  • Justin C. McArthur
  • Susan Morgello
  • David M. Simpson
  • Robert K. Heaton
  • Igor Grant
  • Scott L. Letendre
  • for the CHARTER Group
Article

Abstract

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.

Keywords

Long-term antiretroviral therapy Neurocognitive function Efavirenz Lopinavir/ritonavir Neurotoxicity Hepatitis C virus coinfection 

Notes

Acknowledgments

The CHARTER project is funded by the US National Institutes of Health (HHSN271201000036C, Principal Investigator: Igor Grant). Support to perform the analyses in this manuscript was paid to the University of California, San Diego via an investigator-initiated research grant from Abbvie. Qing Ma, Ph.D. is currently supported by K08MH098794.

The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University, Mount Sinai School of Medicine, University of California, San Diego, University of Texas Medical Branch, Galveston, University of Washington, Seattle, Washington University, St. Louis and is headquartered at the University of California, San Diego and includes Director: Igor Grant, M.D.; Co-Directors: J. Allen McCutchan, M.D., Ronald J. Ellis, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D., Terry Alexander, R.N.; Laboratory, Pharmacology and Immunology Component: Scott Letendre, M.D. (P.I.), Edmund Capparelli, Pharm.D.; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Steven Paul Woods, Psy.D., Matthew Dawson; Virology Component: David M. Smith, M.D. (P.I.); Imaging Component: Christine Fennema-Notestine, Ph.D. (Co-P.I.), Michael J. Taylor, Ph.D. (Co-P.I.), Rebecca Theilmann, Ph.D.; Data Management Unit: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman,; Statistics Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Protocol Coordinating Component: Thomas D. Marcotte, Ph.D. (P.I.), Jennifer Marquie-Beck, M.P.H.; Johns Hopkins University Site: Justin McArthur (P.I.), Vincent Rogalski, R.N.; Icahn School of Medicine at Mount Sinai Site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P.; University of California, San Diego Site: J. Allen McCutchan, M.D. (P.I.), Will Toperoff, N.P.; University of Washington, Seattle Site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Trudy Jones, M.N., A.R.N.P.; University of Texas, Galveston Site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N.; and Washington University, St. Louis Site: David Clifford, M.D. (P.I.), Muhammad Al-Lozi, M.D., Mengesha Teshome, M.D.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the US government.

Author contributions

Dr. Ma is the primary author on this manuscript, and as such, he and Dr. Letendre were responsible for study conceptualization and design. All study data were available to them, and they planned the statistical analyses and performed the interpretation of the results. Drs. Ma and Letendre thereby assume responsibility for the accuracy of the data, analysis, and interpretation. Dr. Vaida assisted with the interpretation of results along with drafting and revising the manuscript. Ms. Wong assisted with the statistical analysis and interpretation of results. Ms. Sanders assisted with data collection, result interpretation, drafting, and revising the manuscript. Ms. Kao assisted with data collection, analysis, and result interpretation. Dr. Croteau made considerable contributions through management and coordination of the data collection and assisted with study design, analysis, and interpretation, as well as revisions to the manuscript. Dr. Clifford assisted with primary data collection, drafting, and revising the manuscript. Dr. Collier assisted with primary data collection, drafting, and revising the manuscript. Dr. Gelman assisted with primary data collection, drafting, and revising the manuscript. Dr. Marra assisted with primary data collection, drafting, and revising the manuscript. Dr. McArthur assisted with primary data collection, drafting, and revising the manuscript. Dr. Morgello assisted with primary data collection, drafting, and revising the manuscript. Dr. Simpson assisted with primary data collection, drafting, and revising the manuscript. Dr. Heaton significantly contributed to all aspects of the manuscript, including study design, statistical analysis, and interpretation of results. He also strongly contributed in revising the manuscript. Dr. Grant assisted with study design, drafting, and revising the manuscript. Dr. Letendre made considerable contributions through management and coordination of the laboratory data and assisted with study design, analysis, and interpretation, as well as revisions to the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest. Q. Ma receives ongoing research support from NIH K08 MH098794. He provided consultancy to McKesson. F. Vaida receives ongoing research support from NIH P30 MH62512, P50 DA26306, R01 MH083552, R01 AI47033, U01 AI74521, R01 MH085608, HHSN271201000030C, HHSN271201000036C, and Precision Photonics Corporation AI068543. Dr. Vaida has also served on a data safety and management board for Ardea Biosciences, Inc. J. Wong, C. Sanders, Y. Kao, and D. Croteau report no disclosures. D. Clifford is supported by NIH grants NS077384, AI69495, DA022137, HHSN271201000036C, NR012907, and the Alzheimer Association. He has also received research support from Lilly, Roche, Pfizer, Bavarian Nordic, and Biogen. In addition, Dr. Clifford has provided scientific advisory or consulting to Amgen, Biogen Idec, Drinker, Biddle and Reath (PML Consortium Scientific Advisory Board), Quintiles, Roche, Genentech, Novartis, GlaxoSmithKline, Millennium, Bristol Meyers Squibb, Genzyme, and Pfizer. A. Collier has ongoing research support from HHSN271201000036C, NIH UM1 AI069434, AI27757, AI057005, and R01 AI090783, current research support from Merck & Company, and past research support from Schering-Plough, Boehringer-Ingelheim, Gilead Sciences, Koronis, and Tibotec-Virco. She and an immediate family member previously owned stock in Abbott Laboratories, Bristol Myers Squibb, Johnson & Johnson, and Pfizer. B. Gelman receives support for NIH grants U24MH100930, R01NS079166, R01NS072005, R01MH101017, and HHSN271201000036C. C. Marra receives research support from the NIH (NINDS and NIMH). She receives royalties from Lippincott Williams & Wilkins and from UptoDate. J. McArthur receives support from HHSN271201000036C. S. Morgello reports no disclosures. D. Simpson receives research support from the NIH (NINDS and NIMH). He provided consultancy to GlaxoSmithKline and Gilead. R. Heaton receives ongoing research support from R01 MH92225, P50 DA26306, P30 MH62512, R01 MH60720, R01 MH58076, R01 MH78737, U01 MH83506, R01 MH83552, R01 MH80150, and HHSN271201000036C. I. Grant receives ongoing research support from NIH P30 MH62512, P50 DA26306, P01 DA12065, U01 MH83506, R01 MH78748, R01 MH83552, NIH/University of Nebraska P01 DA026146, HHSN271201000030C, and HHSN271201000036C. He has also received honoraria from Abbott Pharmaceuticals as part of their Educational Speaker Program. S. Letendre is funded by NIH research awards, including HHSN271201000036C, R01 MH58076, R01 MH92225, P50 DA26306, and P30 MH62512. He has received support for research projects from Abbott, Merck, Tibotec, and GlaxoSmithKline. He has consulted for Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec and has received lecture honoraria from Abbott and Boehringer-Ingelheim.

References

  1. Antinori A, Arendt G, Becker JT et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69(18):1789–1799CrossRefPubMedPubMedCentralGoogle Scholar
  2. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. World Health Organization. Geneva, Switzerland 2006Google Scholar
  3. Beck AT, Steer RA, Brown GK (1996) Manual for the beck depression inventory-II. Psychological Corporation, San AntonioGoogle Scholar
  4. Best BM, Koopmans PP, Letendre SL et al (2011) Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J Antimicrob Chemother 66(2):354–357CrossRefPubMedPubMedCentralGoogle Scholar
  5. Brandmann M, Nehls U, Dringen R (2013) 8-Hydroxy-efavirenz, the primary metabolite of the antiretroviral drug Efavirenz, stimulates the glycolytic flux in cultured rat astrocytes. Neurochem Res 38(12):2524–2534CrossRefPubMedGoogle Scholar
  6. Brown LA, Jin J, Ferrell D et al (2014) 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 9(4):e95500CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bunupuradah T, Chetchotisakd P, Jirajariyavej S et al (2012) Neurocognitive impairment in patients randomized to second-line lopinavir/ritonavir-based antiretroviral therapy vs. lopinavir/ritonavir monotherapy. J Neurovirol 18(6):479–487CrossRefPubMedGoogle Scholar
  8. Capparelli EV, Holland D, Okamoto C et al (2005) Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV. AIDS 19(9):949–952CrossRefPubMedGoogle Scholar
  9. Carey CL, Woods SP, Gonzalez R et al (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26(3):307–319CrossRefPubMedGoogle Scholar
  10. Cherner M, Letendre S, Heaton RK et al (2005) Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology 64(8):1343–1347CrossRefPubMedGoogle Scholar
  11. Ciccarelli N, Fabbiani M, Di Giambenedetto S et al (2011) Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology 76(16):1403–1409CrossRefPubMedGoogle Scholar
  12. Clifford DB, Evans S, Yang Y et al (2005) Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 143(10):714–721CrossRefPubMedGoogle Scholar
  13. Clifford DB, Evans S, Yang Y, Acosta EP, Ribaudo H, Gulick RM (2009) Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials 10(6):343–355CrossRefPubMedPubMedCentralGoogle Scholar
  14. Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8(1):33–44CrossRefPubMedGoogle Scholar
  15. Fletcher NF, Wilson GK, Murray J et al (2012) Hepatitis C virus infects the endothelial cells of the blood–brain barrier. Gastroenterology 142(3):634–643, e6CrossRefPubMedPubMedCentralGoogle Scholar
  16. Garvey LJ, Pavese N, Ramlackhansingh A et al (2012) Acute HCV/HIV coinfection is associated with cognitive dysfunction and cerebral metabolite disturbance, but not increased microglial cell activation. PLoS One 7(7):e38980CrossRefPubMedPubMedCentralGoogle Scholar
  17. Gutierrez F, Navarro A, Padilla S et al (2005) Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis 41(11):1648–1653CrossRefPubMedGoogle Scholar
  18. Heaton RK, Clifford DB, Franklin DR Jr et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75(23):2087–2096CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ikezu T (2009) The aging of human-immunodeficiency-virus-associated neurocognitive disorders. J NeuroImmune Pharm 4(2):161–162CrossRefGoogle Scholar
  20. Justice AC, McGinnis KA, Atkinson JH et al (2004) Psychiatric and neurocognitive disorders among HIV-positive and negative veterans in care: veterans aging cohort five-site study. AIDS 18(Suppl 1):S49–S59CrossRefPubMedGoogle Scholar
  21. Kanmogne GD, Kuate CT, Cysique LA et al (2010) HIV-associated neurocognitive disorders in sub-Saharan Africa: a pilot study in Cameroon. BMC Neurol 10:60CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410(6831):988–994CrossRefPubMedGoogle Scholar
  23. Letendre S (2011) Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med 19(4):137–142PubMedPubMedCentralGoogle Scholar
  24. Letendre SL, Cherner M, Ellis RJ et al (2005) The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance: biological correlates of disease. AIDS 19(Suppl 3):S72–S78CrossRefPubMedGoogle Scholar
  25. Letendre S, Croteau D, Ellis Ret al. Lower CSAR are associated with global neurocognitive impairment in antiretroviral-treated people with HIV. In: 18th Conference on Retroviruses and Opportunistic Infections. Boston, MA, 2011: Abstract 408Google Scholar
  26. Marquine MJ, Umlauf A, Rooney AS et al (2014) The veterans aging cohort study index is associated with concurrent risk for neurocognitive impairment. J Acquir Immune Defic Syndr 65(2):190–197CrossRefPubMedPubMedCentralGoogle Scholar
  27. Morgan EE, Woods SP, Rooney A, Perry W, Grant I, Letendre SL (2012) Intra-individual variability across neurocognitive domains in chronic hepatitis C infection: elevated dispersion is associated with serostatus and unemployment risk. Clin Neuropsychol 26(4):654–674CrossRefPubMedPubMedCentralGoogle Scholar
  28. Robertson K, Liner J, Meeker RB (2012a) Antiretroviral neurotoxicity. J Neurovirol 18(5):388–399CrossRefPubMedPubMedCentralGoogle Scholar
  29. Robertson K, Jiang H, Kumwenda J et al (2012b) Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: AIDS Clinical Trials Group study a5199, the International Neurological Study. Clin Infect Dis 55(6):868–876CrossRefPubMedPubMedCentralGoogle Scholar
  30. Sacktor N, Nakasujja N, Skolasky R et al (2006) Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-Saharan Africa. Neurology 67(2):311–314CrossRefPubMedGoogle Scholar
  31. Santos JR, Munoz-Moreno JA, Molto J et al (2013) Virological efficacy in cerebrospinal fluid and neurocognitive status in patients with long-term monotherapy based on lopinavir/ritonavir: an exploratory study. PLoS One 8(7):e70201CrossRefPubMedPubMedCentralGoogle Scholar
  32. Thiyagarajan A, Garvey LJ, Pflugrad H et al (2010) Cerebral function tests reveal differences in HIV-infected subjects with and without chronic HCV co-infection. Clin Microbiol Infect 16(10):1579–1584CrossRefPubMedGoogle Scholar
  33. Tovar-y-Romo LB, Bumpus NN, Pomerantz D et al (2012) Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J Pharmacol Exp Ther 343(3):696–703CrossRefPubMedPubMedCentralGoogle Scholar
  34. Valcour V, Paul R, Chiao S, Wendelken LA, Miller B (2011) Screening for cognitive impairment in human immunodeficiency virus. Clin Infect Dis 53(8):836–842CrossRefPubMedPubMedCentralGoogle Scholar
  35. Vivithanaporn P, Nelles K, DeBlock L, Newman SC, Gill MJ, Power C (2012) Hepatitis C virus co-infection increases neurocognitive impairment severity and risk of death in treated HIV/AIDS. J Neurol Sci 312(1–2):45–51CrossRefPubMedGoogle Scholar
  36. Winston A, Garvey L, Scotney E et al (2010) Does acute hepatitis C infection affect the central nervous system in HIV-1 infected individuals? J Viral Hepat 17(6):419–426CrossRefPubMedGoogle Scholar
  37. Winston A, Garvey L, Sabin CA (2011) Superior neurocognitive function is associated with central nervous system antiretroviral drug penetration only in regimens containing more than three antiretroviral agents. AIDS 25(7):1014–1015CrossRefPubMedGoogle Scholar
  38. Winston A, Puls R, Kerr SJ et al (2012) Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Med 13(4):245–251PubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2015

Authors and Affiliations

  • Qing Ma
    • 1
    • 7
  • Florin Vaida
    • 1
  • Jenna Wong
    • 1
  • Chelsea A. Sanders
    • 1
  • Yu-ting Kao
    • 1
  • David Croteau
    • 1
  • David B. Clifford
    • 2
  • Ann C. Collier
    • 3
  • Benjamin B. Gelman
    • 4
  • Christina M. Marra
    • 3
  • Justin C. McArthur
    • 5
  • Susan Morgello
    • 6
  • David M. Simpson
    • 6
  • Robert K. Heaton
    • 1
  • Igor Grant
    • 1
  • Scott L. Letendre
    • 1
  • for the CHARTER Group
  1. 1.University of CaliforniaSan DiegoUSA
  2. 2.Washington UniversitySt. LouisUSA
  3. 3.University of WashingtonSeattleUSA
  4. 4.University of Texas Medical BranchGalvestonUSA
  5. 5.Johns Hopkins UniversityBaltimoreUSA
  6. 6.Mount Sinai School of MedicineNew YorkUSA
  7. 7.Department of Pharmacy PracticeUniversity at BuffaloBuffaloUSA

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