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Timing is everything: Antiretroviral nonadherence is associated with impairment in time-based prospective memory

Published online by Cambridge University Press:  01 January 2009

STEVEN PAUL WOODS ,
MATTHEW S. DAWSON ,
ERICA WEBER ,
SARAH GIBSON ,
IGOR GRANT  and
J. HAMPTON ATKINSON
STEVEN PAUL WOODS*
Affiliation:
Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California
MATTHEW S. DAWSON
Affiliation:
Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California
ERICA WEBER
Affiliation:
Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California
SARAH GIBSON
Affiliation:
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California
IGOR GRANT
Affiliation:
Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California
J. HAMPTON ATKINSON
Affiliation:
Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California Psychiatry Service, VA San Diego Healthcare System, San Diego, California
*
*Correspondence and reprint requests to: Steven Paul Woods, HIV Neurobehavioral Research Center, Department of Psychiatry (0847), University of California, San Diego, 150 West Washington Street, 2nd floor, San Diego, California 92103. E-mail: [email protected].
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Abstract

Nonadherence to combination antiretroviral (ARV) therapies (cART) is highly prevalent and significantly increases the risk of adverse human immunodeficiency virus (HIV) disease outcomes. The current study evaluated the hypothesis that prospective memory—a dissociable aspect of episodic memory describing the ability to execute a future intention—plays an important role in successful cART adherence. Seventy-nine individuals with HIV infection who were prescribed at least one ARV medication underwent a comprehensive neuropsychological and neuromedical evaluation prior to completing a 1-month observation of their cART adherence as measured by electronic medication monitoring. Nonadherent individuals (n = 31) demonstrated significantly poorer prospective memory functioning as compared to adherent persons (n = 48), particularly on an index of time-based ProM (i.e., elevated loss of time errors). Deficits in time-based prospective memory were independently predictive of cART nonadherence, even after considering the possible influence of established predictors of adherence, such as general cognitive impairment (e.g., retrospective learning and memory) and psychiatric comorbidity (e.g., depression). These findings extend a nascent literature showing that impairment in time-based prospective memory significantly increases the risk of medication nonadherence and therefore may guide the development of novel strategies for intervention. (JINS, 2009, 15, 42–52.)

Keywords

Human immunodeficiency virusAIDS dementia complexNeuropsychological testsCognitive sciencePatient complianceTime perception
Type
Research Articles
Information
Journal of the International Neuropsychological Society , Volume 15 , Issue 1 , January 2009 , pp. 42 - 52
Copyright
Copyright © INS 2009

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References

REFERENCES

Albert, S.M., Flater, S.R., Clouse, R., Todak, G., Stern, Y., & Marder, K. (2003). Medication management skill in HIV: I. Evidence for adaptation of medication management strategies in people with cognitive impairment. II. Evidence for a pervasive lay model of medication efficacy. AIDS and Behavior, 7, 329–338.CrossRefGoogle ScholarPubMed
Albert, S.M., Weber, C.M., Todak, G., Polanco, C., Clouse, R., McElhiney, M., Rabkin, J., Stern, Y., & Marder, K. (1999). An observed performance test of medication management ability in HIV: Relation to neuropsychological status and medication adherence outcomes. AIDS and Behavior, 3, 121–128.CrossRefGoogle Scholar
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association.Google Scholar
Andrade, A.S., McGruder, H.F., Wu, A.W., Celano, S.A., Skolasky, R.L. Jr., Selnes, O.A., Huang, I.C., & McArthur, J.C. (2005). A programmable prompting device improves adherence to highly active antiretroviral therapy in HIV-infected subjects with memory impairment. Clinical Infectious Diseases, 41, 875–882.CrossRefGoogle ScholarPubMed
Antinori, A., Arendt, G., Becker, J.T., Brew, B.J., Byrd, D.A., Cherner, M., Clifford, D.B., Cinque, P., Epstein, L.G., Goodkin, K., Gisslen, M., Grant, I., Heaton, R.K., Joseph, J., Marder, K., Marra, C.M., McArthur, J.C., Nunn, M., Price, R.W., Pulliam, L., Robertson, K.R., Sacktor, N., Valcour, V., & Wojna, V.E. (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology, 69, 1789–1799.CrossRefGoogle ScholarPubMed
Avants, S.K., Margolin, A., Warburton, L.A., Hawkins, K.A., & Shi, J. (2001). Predictors of nonadherence to HIV-related medication regimens during methadone stabilization. The American Journal on Addictions, 10, 69–78.CrossRefGoogle ScholarPubMed
Bangsburg, D.R. (2008). Preventing HIV antiretroviral resistance through better monitoring of treatment adherence. Journal of Infectious Diseases, 197(Suppl 3), 272–278.CrossRefGoogle Scholar
Barclay, T.R., Hinkin, C.H., Castellon, S.A., Mason, K.I., Reinhard, M.J., Marion, S.D., Levine, A.J., & Durvasula, R.S. (2007). Age-associated predictors of medication adherence in HIV-positive adults: Health beliefs, self-efficacy, and neurocognitive status. Health Psychology, 26, 40–49.CrossRefGoogle ScholarPubMed
Barkley, R.A., Murphy, K.R., & Bush, T. (2001). Time perception and reproduction in young adults with attention deficit hyperactivity disorder. Neuropsychology, 15(3), 351–360.CrossRefGoogle ScholarPubMed
Benedict, R.H.B., Mexhir, J.J., Walsh, K., & Hewitt, R.G. (2000). Impact of human immunodeficiency virus type-1-associated cognitive dysfunction on activities of daily living and quality of life. Archives of Clinical Neuropsychology, 15, 529–534.CrossRefGoogle ScholarPubMed
Benton, A.L., Hamsher, K., & Sivan, A.B. (1994). Multilingual aphasia examination. Iowa City, IA: AJA Associates.Google Scholar
Bieliauskas, L.A., Fastenau, P.S., Lacy, M.A., & Roper, B.L. (1997). Use of the odds ratio to translate neuropsychological test scores into real-world outcomes: From statistical significance to clinical significance. Journal of Clinical and Experimental Neuropsychology, 19, 889–896.CrossRefGoogle ScholarPubMed
Bova, C.A., Fennie, K.P., Knafl, G.J., Dieckhaus, K.D., Watrous, E., & Willimas, A.B. (2005). Use of electronic monitoring devices to measure antiretroviral adherence: Practical considerations. AIDS and Behavior, 9, 103–110.CrossRefGoogle ScholarPubMed
Butters, N., Grant, I., Haxby, J., Judd, L.L., Martin, A., McClelland, J., Pequegnat, W., Schacter, D., & Stover, E. (1990). Assessment of AIDS-related cognitive changes: Recommendations of the NIMH workshop on neuropsychological assessment approaches. Journal of Clinical and Experimental Neuropsychology, 12, 963–978.CrossRefGoogle ScholarPubMed
Carey, C.L., Woods, S.P., Rippeth, J.D., Heaton, R.K., Grant, I., & The HNRC Group (2006). Prospective memory in HIV-1 infection. Journal of Clinical and Experimental Neuropsychology, 28, 536–548.CrossRefGoogle ScholarPubMed
Centers for Disease Control and Prevention. (2006). HIV/AIDS surveillance Report, 2005, Vol. 17. Atlanta, GA: U.S. Department of Health and Human Services, Center for Disease Control and Prevention.Google Scholar
Chesney, M.A., Ickovics, J.R., Chambers, D.B., Gifford, A.L., Neidig, J., Zwickl, B., & Wu, A.W. (2000). Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: The AACTG adherence instruments. Patient Care Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG). AIDS Care, 12, 255–266.CrossRefGoogle Scholar
Culbertson, W.C. & Zillmer, E.A. (2001). The Tower of London DX (TOL-DX) manual. North Tonawanda, NY: Multi-Health Systems.Google Scholar
Delis, D.C., Kramer, J.H., Kaplan, E., & Ober, B.A. (2000). The California Verbal Learning Test (2nd ed.). San Antonio, TX: The Psychological Corporation.Google Scholar
DiIorio, C., McCarty, F., Depadilla, L., Resnicow, K., Holstad, M.M., Yeager, K., Sharma, S.M., Morisky, D.E., & Lundberg, B. (in press). Adherence to antiretroviral medication regimens: A test of a psychosocial model. AIDS and Behavior.Google Scholar
Fish, J., Evans, J.J., Nimmo, M., Martin, E., Kersel, D., Bateman, A., Wilson, B.A., & Manly, T. (2007). Rehabilitation of executive dysfunction following brain injury: “Content-free” cueing improves everyday prospective memory performance. Neuropsychologia, 45(6), 1318–1330.CrossRefGoogle ScholarPubMed
Gould, O.N., McDonald-Miszczak, L., & King, B. (1997). Metacognition and medication adherence: How do older adults remember? Experimental Aging Research, 23, 315–342.CrossRefGoogle ScholarPubMed
Harrigan, P.R., Hogg, R.S., Dong, W.W., Yup, B., Wynhoven, B., Woodward, J., Brumme, C.J., Brumme, Z.L., Mo, T., Alexander, C.S., & Montaner, J.S. (2005). Predictors of HIV drug-resistance mutations in a large antiretroviral-naïve cohort initiating triple antiretroviral therapy. Journal of Infectious Diseases, 191, 339–347.CrossRefGoogle Scholar
Heaton, R.K., Grant, I., Butters, N., White, D.A., Kirson, D., Atkinson, J.H., McCutchan, J.A., Taylor, M.J., Kelly, M.D., & Ellis, R.J. (1995). The HNRC 500: Neuropsychology of HIV infection at different disease stages. Journal of the International Neuropsychological Society, 1, 231–251.CrossRefGoogle ScholarPubMed
Heaton, R.K., Marcotte, T.D., Mindt, M.R., Sadek, J., Moore, D.J., Bentley, H., McCutchan, J.A., Reicks, C., Grant, I., & The HNRC Group. (2004). The impact of HIV-associated neuropsychological impairment on everyday functioning. Journal of the International Neuropsychological Society, 10, 317–331.CrossRefGoogle ScholarPubMed
Hertzog, C., Park, D., Morell, R.W., & Martin, M. (2000). Ask and ye shall receive: Behavioural specificity in the accuracy of subjective memory complaints. Applied Cognitive Psychology, 14, 257–275.3.0.CO;2-O>CrossRefGoogle Scholar
Hinkin, C.H., Barclay, T.R., Castellon, S.A., Levine, A.J., Durvasula, R.S., Marion, S.D., Myers, H.F., & Longshore, D. (2007). Drug use and medication adherence among HIV-1 infected individuals. AIDS and Behavior, 11, 185–194.CrossRefGoogle ScholarPubMed
Hinkin, C.H., Castellon, S.A., Durvasula, R.S., Hardy, D.J., Lam, M.N., Mason, K.I., Thrasher, D., Goetz, M.B., & Stefaniak, M. (2002). Medication adherence among HIV+ adults: Effects of cognitive dysfunction and regimen complexity. Neurology, 59, 1944–1950.CrossRefGoogle ScholarPubMed
Hinkin, C.H., Hardy, D.J., Mason, K.I., Castellon, S.A., Durvasula, R.S., Lam, M.N., & Stefaniak, M. (2004). Medication adherence in HIV-infected adults: Effect of patient age, cognitive status, and substance abuse. AIDS, 18, S19–S25.CrossRefGoogle ScholarPubMed
Ivnik, R.J., Smith, G.E., Petersen, R.C., Boeve, B.F., Kokmen, E., & Tangalos, E.G. (2000). Diagnostic accuracy of four approaches to interpreting neuropsychological test data. Neuropsychology, 14, 163–177.CrossRefGoogle ScholarPubMed
Kløve, H. (1963). Grooved pegboard. Indiana: Lafayette Instruments.Google Scholar
Leirer, V.O., Morrow, D.G., Tanke, E.D., & Pariante, G.M. (1991). Elders’ nonadherence: Its assessment and medication reminding by voice mail. The Gerontologist, 31, 514–520.CrossRefGoogle ScholarPubMed
Levine, A.J., Hinkin, C.H., Marion, S., Keuning, A., Castellon, S.A., Lam, M.M., Robinet, M., Longshore, D., Newton, T., Myers, H., & Durvasula, R.S. (2006). Adherence to antiretroviral medications in HIV: Differences in data collected via self-report and electronic monitoring. Health Psychology, 25, 329–335.CrossRefGoogle ScholarPubMed
Levine, B., Robertson, I.H., Clare, L., Carter, G., Hong, J., Wilson, B.A., Duncan, J., & Stuss, D.T. (2000). Rehabilitation of executive functioning: An experimental-clinical validation of goal management training. Journal of the International Neuropsychological Society, 6, 299–312.CrossRefGoogle ScholarPubMed
Lima, V.D., Geller, J., Bangsberg, D.R., Patterson, T.L., Daniel, M., & Kerr, T. (2007). The effect of adherence on the association between depressive symptoms and mortality among HIV-infected individuals first initiating HAART. AIDS, 21, 1175–1183.CrossRefGoogle ScholarPubMed
Liu, C., Ostrow, D., Detels, R., Hu, Z., Johnson, L., Kingsley, L., & Jacobson, L.P. (2006). Impacts of HIV infection and HAART use on quality of life. Quality of Life Research, 15, 941–949.CrossRefGoogle ScholarPubMed
Mäntylä, T. & Carelli, M.G. (2006). Time monitoring and executive functioning: Individual and developmental differences. In Glicksohn, J. & Myslobodsky, M.S. (Eds.), Timing the future: The case for a time-based prospective memory (pp. 191–211). River Edge, NJ: World Scientific Publishing Co.CrossRefGoogle Scholar
Martin, E.M., Nixon, H., Pitrak, D.L., Weddington, W., Rains, N.A., Nunnally, G., Grbesic, S., Gonzalez, R., Jacobus, J., & Bechara, A. (2007). Characteristics of prospective memory deficits in HIV-seropositive substance-dependent individuals: Preliminary observations. Journal of Clinical and Experimental Neuropsychology, 29, 496–504.CrossRefGoogle ScholarPubMed
McDaniel, M.A. & Einstein, G.O. (2007). Prospective memory: An overview and synthesis of an emerging field. Thousand Oaks, CA: Sage Publications.CrossRefGoogle Scholar
McDonald-Miszczak, L., Maris, P., Fitzgibbon, T., & Ritchie, G. (2004). A pilot study examining older adults’ beliefs related to medication adherence: The BERMA Survey. Journal of Aging and Health, 16, 591–614.CrossRefGoogle ScholarPubMed
McNair, D.M., Lorr, M., & Droppleman, L.F. (1981). Manual for the profile of mood states. San Diego, CA: Educational and Industrial Testing Service.Google Scholar
Meck, W.H. (2005). Neuropsychology of timing and time perception. Brain and Cognition, 58, 1–8.CrossRefGoogle ScholarPubMed
Mimura, M., Kinsbourne, M., & O’Connor, M. (2000). Time estimation by patients with frontal lesions and by Korsakoff amnesics. Journal of the International Neuropsychological Society, 6, 517–528.CrossRefGoogle ScholarPubMed
Morgan, E.E., Woods, S.P., Weber, E., Dawson, M.S., Carey, C.L., Moran, L.M., Grant, I., & The HNRC Group. (in press). HIV-associated episodic memory impairment: Evidence of a possible differential deficit in source memory for complex visual stimuli. Journal of Neuropsychiatry and Clinical Neurosciences.Google Scholar
Nieuwkerk, P.T., Sprangers, M.A., Burger, D.M., Hoetelmans, R.M., Hugen, P.W., Danner, S.A., van der Ende, M.E., Schneider, M.M., Schrey, G., Meenhorst, P.L., Sprenger, H.G., Kaufmann, R.H., Jambroes, M., Chesney, M.A., de Wolf, F., Lange, J.M., & The ATHENA Project. (2001). Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. Archives of Internal Medicine, 161, 1962–1968.CrossRefGoogle Scholar
Osterberg, L. & Blaschke, T. (2005). Adherence to medication. New England Journal of Medicine, 353, 487–497.CrossRefGoogle ScholarPubMed
Paterson, D.L., Potoski, B., & Capitano, B. (2002). Measurement of adherence to antiretroviral medications. Journal of Acquired Immune Deficiency Syndrome, 15, S103–S106.CrossRefGoogle Scholar
Perno, C.F., Ceccherini-Silberstein, F., De Luca, A., Cozzi-Lepri, A., Gori, C., Cingolani, A., Bellocchi, M.C., Trotta, M.P., Piano, P., Forbici, F., Scasso, A., Vullo, V., d’Arminio Monforte, A., Antinori, A., & The AdICoNA Study Group. (2002). Virologic correlates of adherence to antiretroviral medications and therapeutic failure. Journal of Acquired Immune Deficiency Syndrome, 31, S118–S122.CrossRefGoogle ScholarPubMed
Psychological Corporation. (1997). WAIS-III and WMS-III technical manual. San Antonio, TX: Psychological Corporation.Google Scholar
Psychological Corporation. (2001). Wechsler Test of Adult Reading. San Antonio, TX: Psychological Corporation.Google Scholar
Raskin, S. (2004). Memory for intentions screening test [abstract]. Journal of the International Neuropsychological Society, 10(Suppl 1), 110.Google Scholar
Reitan, R.M. & Wolfson, D. (1985). The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation. Tucson, AZ: Neuropsychology Press.Google Scholar
Robertson, K.R., Smurzynski, M., Parsons, T.D., Wu, K., Bosch, R.J., Wu, J., McCartur, J.C., Collier, A.C., Evans, S.R., & Ellis, R.J. (2007). The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS, 21, 915–921.CrossRefGoogle ScholarPubMed
Shimamura, A.P. & Jurica, P.J. (1994). Memory interference effects and aging: Findings from a test of frontal lobe function. Neuropsychology, 8, 408–412.CrossRefGoogle Scholar
Shum, D., Ungvari, G.S., Tang, W.K., & Leung, J.P. (2004). Performance of schizophrenia patients on time-, event-, and activity-based prospective memory tasks. Schizophrenia Bulletin, 30, 693–701.CrossRefGoogle ScholarPubMed
Simoni, J.M., Frick, P.A., Pantalone, D.W., & Turner, B.J. (2003). Antiretroviral adherence interventions: A review of current literature and ongoing studies. Topics in HIV Medicine, 11, 185–198.Google Scholar
Smith, G., Della Sala, S., Logie, R.H., & Maylor, E.A. (2000). Prospective and retrospective memory in normal aging and dementia: A questionnaire study. Memory, 8, 311–321.CrossRefGoogle ScholarPubMed
Stern, R.A., Javorsky, D.J., Singer, E.A., Singer Harris, N.G., Somerville, J.A., Duke, L.M., Thompson, J.A., & Kaplan, E. (1999). The Boston Qualitative Scoring System for the Rey-Osterrieth Complex Figure (BQSS): Manual. Lutz, FL: Psychological Assessment Resources, Inc.Google Scholar
Twamley, E.W., Woods, S.P., Zurhellen, C.H., Vertinski, M., Narvaez, J.M., Mausbach, B.T., Patterson, T.L., & Jeste, D.V. (2008). Neuropsychological substrates and everyday functioning implications of prospective memory impairment in schizophrenia. Schizophrenia Research, 106, 42–49.CrossRefGoogle ScholarPubMed
van den Broek, M.D., Downes, J., Johnson, Z., Dayus, B., & Hilton, N. (2000). Evaluation of an electronic memory aid in the neuropsychological rehabilitation of prospective memory deficits. Brain Injury, 14, 455–462.CrossRefGoogle ScholarPubMed
Vedhara, K., Wadsworth, E., Norman, P., Searle, A., Mitchel, J., Macrae, N., O’Mahony, M., Kemple, T., & Memel, D. (2004). Habitual prospective memory in elderly patients with type 2 diabetes: Implications for medication adherence. Psychology, Health & Medicine, 9, 17–27.CrossRefGoogle Scholar
Wagner, G.J. (2002). Predictors of antiretroviral adherence as measured by self-report, electronic monitoring, and medication diaries. AIDS Patient Care STDs, 16, 599–608.CrossRefGoogle ScholarPubMed
Waldrop-Valverde, D., Ownby, R.L., Wilkie, F.L., Mack, A., Kumar, M., & Metsch, L. (2006). Neurocognitive aspects of medication adherence in HIV-positive injecting drug users. AIDS and Behavior, 10, 287–297.CrossRefGoogle ScholarPubMed
Woods, S.P., Carey, C.L., Moran, L.M., Dawson, M.S., Letendre, S.L., Grant, I., & The HNRC Group. (2007a). Frequency and predictors of self-reported memory complaints in individuals infected with HIV. Archives of Clinical Neuropsychology, 22, 187–195.CrossRefGoogle ScholarPubMed
Woods, S.P., Dawson, M.S., Carey, C.L., Morgan, E.E., Scott, J.C., Grant, I., & The HNRC Group. (2006a). Increased cognitive load exacerbates HIV-1-associated time-based prospective memory impairment [abstract]. Journal of the International Neuropsychological Society, 12(Suppl 1), 148.Google Scholar
Woods, S.P., Iudicello, J.E., Moran, L.M., Carey, C.L., Dawson, M.S., Grant, I., & The HNRC Group. (2008a). HIV-associated prospective memory impairment increases risk of dependence in everyday functioning. Neuropsychology, 22, 110–117.CrossRefGoogle ScholarPubMed
Woods, S.P., Moran, L.M., Carey, C.L., Dawson, M.S., Iudicello, J.E., Gibson, S., Grant, I., Atkinson, J.H., & The HNRC Group. (2008b). Prospective memory in HIV infection: Is “remembering to remember” a unique predictor of self-reported medication management? Archives of Clinical Neuropsychology, 23, 257–270.CrossRefGoogle Scholar
Woods, S.P., Moran, L.M., Dawson, M.S., Carey, C.L., Grant, I., & The HNRC Group. (2008). Psychometric characteristics of the Memory for Intentions Screening Test. The Clinical Neuropsychologist, 22, 864–878.CrossRefGoogle ScholarPubMed
Woods, S.P., Morgan, E.E., Marquie-Beck, J., Carey, C.L., Grant, I., Letendre, S.L., & The HNRC Group. (2006b). Markers of macrophage activation and axonal injury are associated with prospective memory in HIV-1 disease. Cognitive & Behavioral Neurology, 19, 217–221.CrossRefGoogle ScholarPubMed
Woods, S.P., Rippeth, J.D., Frol, A.B., Levy, J.K., Ryan, E., Soukup, V.M., Hinkin, C.H., Lazzaretto, D., Cherner, M., Marcotte, T.D., Gelman, B.B., Morgello, S., Singer, E.J., Grant, I., & Heaton, R.K. (2004). Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. Journal of Clinical and Experimental Neuropsychology, 26, 759–778.CrossRefGoogle ScholarPubMed
Woods, S.P., Scott, J.C., Sires, D.A., Grant, I., Heaton, R.K., Tröster, A.I., & The HNRC Group. (2005). Action (verb) fluency: Test-retest reliability, normative standards, and construct validity. Journal of the International Neuropsychological Society, 11, 408–415.CrossRefGoogle ScholarPubMed
Woods, S.P., Twamley, E.W., Dawson, M.S., Narvaez, J.M., & Jeste, D.V. (2007b). Deficits in cue detection and intention retrieval underlie prospective memory impairment in schizophrenia. Schizophrenia Research, 90, 344–350.CrossRefGoogle ScholarPubMed
World Health Organization. (1998). Composite international diagnostic interview (CIDI, version 2.1). Geneva, Switzerland: World Health Organization.Google Scholar