Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients
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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.
KeywordsLong-term antiretroviral therapy Neurocognitive function Efavirenz Lopinavir/ritonavir Neurotoxicity Hepatitis C virus coinfection
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.
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.
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