Journal of NeuroVirology

, Volume 23, Issue 4, pp 550–557 | Cite as

The nature and consequences of cognitive deficits among tobacco smokers with HIV: a comparison to tobacco smokers without HIV

  • Joseph D. Harrison
  • Jessica A. Dochney
  • Sonja Blazekovic
  • Frank Leone
  • David Metzger
  • Ian Frank
  • Robert Gross
  • Anita Hole
  • Karam Mounzer
  • Steven Siegel
  • Robert A. Schnoll
  • Rebecca L. Ashare


HIV-infected smokers lose more years of life to tobacco-related disease than HIV. Since neurocognitive deficits are common among those with HIV and are associated with smoking persistence, these deficits may be a unique barrier to smoking cessation among HIV-infected smokers. Documenting unique differences in and correlates of cognition among HIV-infected smokers is a critical step towards developing a population-specific tobacco cessation treatment. We compared neurocognitive function between HIV-infected (n = 103) and HIV-uninfected smokers (n = 70), accounting for demographic and smoking-related variables. We also evaluated whether HIV-related health outcomes (e.g., CD4 count, viral load, depression ratings, quality of life [QoL]) and HAART adherence were associated with cognition. Participants completed neurocognitive tasks (N-back and Continuous Performance Task [CPT]) measuring working memory, attention, and processing speed, and intra-individual variability. Stepwise regression models were conducted and validated with resampling techniques. HIV-infected smokers performed worse than HIV-uninfected smokers on working memory, processing speed, and intra-individual variability (all p < 0.01). ROC analysis for the model including cognitive measures demonstrated 85% area under the curve, which indicates “good prediction” for distinguishing between HIV-infected and HIV-uninfected smokers. This was a significant improvement over the model including demographic and smoking-related variables only (p = 0.0003). Among HIV-infected smokers, neurocognitive performance was negatively associated with QoL and depression ratings. Smoking cessation interventions for HIV-infected smokers should consider cognitive neurorehabilitation as a potential strategy to decrease the likelihood of nicotine relapse and decrease tobacco-related morbidity in this population.


Smoking cessation HIV Cognition HIV-associated neurocognitive disorder Tobacco use 



This research was supported by grants from the National Institute on Drug Abuse (R01 DA033681 and K23 DA035295) and through core services and support from the Penn Center for AIDS Research (P30 AI045008) and Penn Mental Health AIDS Research Center (P30 MH097488).

Compliance with ethical standards

Conflict of interest

Dr. Schnoll receives medication and placebo free from Pfizer and has provided consultation to Pfizer and GlaxoSmithKline. These companies had no involvement in this study.

Dr. Siegel has received grants and/or has acted as a consultant to Astellas, Merck, and Zynerba that is unrelated to the content of this manuscript.

Dr. Gross sits on a Data Safety and Management Board for a Pfizer drug treating inflammatory bowel disease that is unrelated to the contents of this manuscript.


  1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ashare RL, Falcone M, Lerman C (2014a) Cognitive function during nicotine withdrawal: implications for nicotine dependence treatment. Neuropharmacology 76:581–591CrossRefPubMedGoogle Scholar
  3. Ashare RL, Schmidt HD (2014) Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal. Expert Opin Drug Discov 9:579–594CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ashare RL, Strasser AA, Wileyto EP, Cuevas J, Audrain-McGovern J (2014b) Cognitive deficits specific to depression-prone smokers during abstinence. Exp Clin Psychopharmacol 22:323–331CrossRefPubMedPubMedCentralGoogle Scholar
  5. Austin PC, Tu JV (2004) Bootstrap methods for developing predictive models. Am Stat 58:131–137CrossRefGoogle Scholar
  6. Bradley AP (1997) The use of the area under the ROC curve in the evaluation of machine learning algorithms. Pattern Recogn 30:1145–1159CrossRefGoogle Scholar
  7. Bryant VE, Kahler CW, Devlin KN, Monti PM, Cohen RA (2013) The effects of cigarette smoking on learning and memory performance among people living with HIV/AIDS. AIDS Care 25:1308–1316CrossRefPubMedPubMedCentralGoogle Scholar
  8. Coste J, Quinquis L, D'Almeida S, Audureau E (2014) Smoking and health-related quality of life in the general population. Independent relationships and large differences according to patterns and quantity of smoking and to gender. PLoS One 9:e91562CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cysique LA, Letendre SL, Ake C, Jin H, Franklin DR, Gupta S, Shi C, Yu X, Wu Z, Abramson IS, Grant I, Heaton RK (2010) Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China. AIDS 24:983–990CrossRefPubMedPubMedCentralGoogle Scholar
  10. Deeken JF, Tjen ALA, Rudek MA, Okuliar C, Young M, Little RF, Dezube BJ (2012) The rising challenge of non-AIDS-defining cancers in HIV-infected patients. Clin Infect Dis 55:1228–1235CrossRefPubMedPubMedCentralGoogle Scholar
  11. Doyle KL, Morgan EE, Morris S, Smith DM, Little S, Iudicello JE, Blackstone K, Moore DJ, Grant I, Letendre SL, Woods SP (2013) Real-world impact of neurocognitive deficits in acute and early HIV infection. J Neuro-Oncol 19:565–573Google Scholar
  12. Durazzo TC, Meyerhoff DJ, Nixon SJ (2012) A comprehensive assessment of neurocognition in middle-aged chronic cigarette smokers. Drug Alcohol Depend 122:105–111CrossRefPubMedGoogle Scholar
  13. Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, Collier AC, Gelman B, McArthur J, Morgello S, McCutchan JA, Grant I (2011). CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS (London, England) 25:  10.1097/QAD.0b013e32834a40cd.
  14. Evans DE, Drobes DJ (2009) Nicotine self-medication of cognitive-attentional processing. Addict Biol 14:32–42CrossRefPubMedGoogle Scholar
  15. Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Collier AC, Marra CM, Clifford DB, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Smith DM, Heaton RK (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055–2062CrossRefPubMedPubMedCentralGoogle Scholar
  16. Green A, Ellis KA, Ellis J, Bartholomeusz CF, Ilic S, Croft RJ, Phan KL, Nathan PJ (2005) Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans. Pharmacol Biochem Behav 81:575–584CrossRefPubMedGoogle Scholar
  17. Hakkers CS, Arends JE, Barth RE, Du Plessis S, Hoepelman AI, Vink M (2016). Review of functional MRI in HIV: effects of aging and medication. J Neurovirol.Google Scholar
  18. Harrell FE Jr, Lee KL, Mark DB (1996) Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 15:361–387CrossRefPubMedGoogle Scholar
  19. Health PDoP (2015). AIDS Activities Coordinating Office Surveillance Report, 2014. Philadelphia, PA: City of Philadelphia.Google Scholar
  20. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 86:1119–1127CrossRefPubMedGoogle Scholar
  21. Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neuro-Oncol 17:3–16Google Scholar
  22. Heaton RK, Franklin DR Jr, Deutsch R, Letendre S, Ellis RJ, Casaletto K, Marquine MJ, Woods SP, Vaida F, Atkinson JH, Marcotte TD, McCutchan JA, Collier AC, Marra CM, Clifford DB, Gelman BB, Sacktor N, Morgello S, Simpson DM, Abramson I, Gamst AC, Fennema-Notestine C, Smith DM, Grant I (2015) Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis 60:473–480CrossRefPubMedGoogle Scholar
  23. Helleberg M, Afzal S, Kronborg G, Larsen CS, Pedersen G, Pedersen C, Gerstoft J, Nordestgaard BG, Obel N (2013) Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis 56:727–734CrossRefPubMedGoogle Scholar
  24. Hilborn JV, Strauss E, Hultsch DF, Hunter MA (2009) Intraindividual variability across cognitive domains: investigation of dispersion levels and performance profiles in older adults. J Clin Exp Neuropsychol 31:412–424CrossRefPubMedGoogle Scholar
  25. Holmes WC, Shea JA (1998) A new HIV/AIDS-targeted quality of life (HAT-QoL) instrument: development, reliability, and validity. Med Care 36:138–154CrossRefPubMedGoogle Scholar
  26. Hosmer DW, Lemeshow S (2000) Applied logistic regression. Wiley-Interscience, HobokenCrossRefGoogle Scholar
  27. Hunt PW, Lee SA, Siedner MJ (2016) Immunologic biomarkers, morbidity, and mortality in treated HIV infection. J Infect Dis 214(Suppl 2):S44–S50CrossRefPubMedGoogle Scholar
  28. Kurtz MM, Ragland JD, Bilker W, Gur RC, Gur RE (2001) Comparison of the continuous performance test with and without working memory demands in healthy controls and patients with schizophrenia. Schizophr Res 48:307–316CrossRefPubMedGoogle Scholar
  29. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW (2013) Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 119:51–83CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lieberman JA, Dunbar G, Segreti AC, Girgis RR, Seoane F, Beaver JS, Duan N, Hosford DA (2013) A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology 38:968–975CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lindl KA, Marks DR, Kolson DL, Jordan-Sciutto KL (2010) HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J NeuroImmune Pharmacol 5:294–309CrossRefPubMedPubMedCentralGoogle Scholar
  32. Loughead J, Wileyto EP, Ruparel K, Falcone M, Hopson R, Gur R, Lerman C (2015) Working memory-related neural activity predicts future smoking relapse. Neuropsychopharmacology 40:1311–1320CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ma Q, Vaida F, Wong J, Sanders CA, Kao YT, Croteau D, Clifford DB, Collier AC, Gelman BB, Marra CM, McArthur JC, Morgello S, Simpson DM, Heaton RK, Grant I, Letendre SL (2016) Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neuro-Oncol 22:170–178Google Scholar
  34. Mahy M, Autenrieth CS, Stanecki K, Wynd S (2014) Increasing trends in HIV prevalence among people aged 50 years and older: evidence from estimates and survey data. AIDS (London, England) 28:S453–S459CrossRefGoogle Scholar
  35. Manda VK, Mittapalli RK, Geldenhuys WJ, Lockman PR (2010) Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrity. J Neurochem 115:515–525CrossRefPubMedGoogle Scholar
  36. Monnig MA, Kahler CW, Lee H, Pantalone DW, Mayer KH, Cohen RA, Monti PM (2016) Effects of smoking and alcohol use on neurocognitive functioning in heavy drinking, HIV-positive men who have sex with men. AIDS Care 28:300–305CrossRefPubMedGoogle Scholar
  37. Moore RC, Fazeli PL, Jeste DV, Moore DJ, Grant I, Woods SP (2014) Successful cognitive aging and health-related quality of life in younger and older adults infected with HIV. AIDS Behav 18:1186–1197CrossRefPubMedPubMedCentralGoogle Scholar
  38. Morgan EE, Woods SP, Delano-Wood L, Bondi MW, Grant I (2011) Intraindividual variability in HIV infection: evidence for greater neurocognitive dispersion in older HIV seropositive adults. Neuropsychology 25:645–654CrossRefPubMedPubMedCentralGoogle Scholar
  39. Nahvi S, Cooperman NA (2009) Review: the need for smoking cessation among HIV-positive smokers. AIDS Educ Prev 21:14–27CrossRefPubMedPubMedCentralGoogle Scholar
  40. Pacek LR, Cioe PA (2015) Tobacco use, use disorders, and smoking cessation interventions in persons living with HIV. Curr HIV/AIDS Rep 12:413–420CrossRefPubMedPubMedCentralGoogle Scholar
  41. Patterson F, Jepson C, Strasser AA, Loughead J, Perkins KA, Gur RC, Frey JM, Siegel S, Lerman C (2009) Varenicline improves mood and cognition during smoking abstinence. Biol Psychiatry 65:144–149CrossRefPubMedGoogle Scholar
  42. Paul RH, Brickman AM, Cohen RA, Williams LM, Niaura R, Pogun S, Clark CR, Gunstad J, Gordon E (2006) Cognitive status of young and older cigarette smokers: data from the international brain database. J Clin Neurosci 13:457–465CrossRefPubMedGoogle Scholar
  43. Robertson K, Yosief S (2014) Neurocognitive assessment in the diagnosis of HIV-associated neurocognitive disorders. Semin Neurol 34:21–26CrossRefPubMedGoogle Scholar
  44. Rubinstein PG, Aboulafia DM, Zloza A (2014) Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges. AIDS 28:453–465CrossRefPubMedPubMedCentralGoogle Scholar
  45. Sacktor N, Skolasky RL, Seaberg E, Munro C, Becker JT, Martin E, Ragin A, Levine A, Miller E (2016) Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology 86:334–340CrossRefPubMedPubMedCentralGoogle Scholar
  46. Schouten J, Wit FW, Stolte IG, Kootstra NA, van der Valk M, Geerlings SE, Prins M, Reiss P (2014) Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis 59:1787–1797CrossRefPubMedGoogle Scholar
  47. Shirley DK, Kaner RJ, Glesby MJ (2013) Effects of smoking on non-AIDS-related morbidity in HIV-infected patients. Clin Infect Dis 57:275–282CrossRefPubMedPubMedCentralGoogle Scholar
  48. Snodgrass JG, Corwin J (1988) Pragmatics of measuring recognition memory: applications to dementia and amnesia. Journal of Experimental Psychology-General 117:34–50CrossRefPubMedGoogle Scholar
  49. Stampfli MR, Anderson GP (2009) How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol 9:377–384CrossRefPubMedGoogle Scholar
  50. Steyerberg E (2008). Clinical prediction models: a practical approach to development, validation, and updating. Springer Science & Business Media.Google Scholar
  51. Thaler NS, Sayegh P, Arentoft A, Thames AD, Castellon SA, Hinkin CH (2015) Increased neurocognitive intra-individual variability is associated with declines in medication adherence in HIV-infected adults. Neuropsychology 29:919–925CrossRefPubMedPubMedCentralGoogle Scholar
  52. Weber E, Blackstone K, Woods SP (2013) Cognitive neurorehabilitation of HIV-associated neurocognitive disorders: a qualitative review and call to action. Neuropsychol Rev 23:81–98CrossRefPubMedPubMedCentralGoogle Scholar
  53. Weiland BJ, Sabbineni A, Calhoun VD, Welsh RC, Hutchison KE (2015) Reduced executive and default network functional connectivity in cigarette smokers. Hum Brain Mapp 36:872–882CrossRefPubMedGoogle Scholar
  54. Zachary RS (2000). Shipley Institute of Living Scale - Revised Manual. Western Psychological Services.Google Scholar
  55. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2017

Authors and Affiliations

  • Joseph D. Harrison
    • 1
  • Jessica A. Dochney
    • 1
  • Sonja Blazekovic
    • 1
  • Frank Leone
    • 2
  • David Metzger
    • 1
  • Ian Frank
    • 3
  • Robert Gross
    • 3
    • 4
  • Anita Hole
    • 1
  • Karam Mounzer
    • 5
  • Steven Siegel
    • 6
  • Robert A. Schnoll
    • 7
  • Rebecca L. Ashare
    • 1
  1. 1.Department of PsychiatryUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  2. 2.Pulmonary, Allergy, & Critical Care DivisionUniversity of Pennsylvania Presbyterian Medical CenterPhiladelphiaUSA
  3. 3.Division of Infectious DiseasesUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  4. 4.Center for Clinical Epidemiology and BiostatisticsUniversity of PennsylvaniaPhiladelphiaUSA
  5. 5.Philadelphia FightPhiladelphiaUSA
  6. 6.Department of Psychiatry and Behavioral SciencesKeck School of Medicine of the University of Southern CaliforniaLos AngelesUSA
  7. 7.Department of Psychiatry and Abramson Cancer CenterUniversity of PennsylvaniaPennsylvaniUSA

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