Abstract
Although no longer considered therapeutically beneficial, antiretroviral treatment interruptions (TIs) still occur frequently among patients with human immunodeficiency virus (HIV) infection for a variety of reasons. TIs typically result in viral rebound and worsening immunosuppression, which in turn are risk factors for neurocognitive decline and dementia. We sought to determine the extent of neurocognitive risk with TIs and subsequent reintroduction of highly active antiretroviral therapy (HAART) by using a comprehensive, sensitive neuropsychological assessment and by concurrently determining changes in plasma and cerebrospinal fluid (CSF) viral load and CD4 counts. Prospective, serial, clinical evaluations including neuropsychological (NP) testing and measurement of plasma HIV RNA and CD4 count and mood state were performed on HIV-1—infected individuals (N=11) at three time points: (1) prior to a TI, while on HAART; (2) after TIs averaging 6 months; and (3) after reinitiating HAART therapy. During TI, plasma HIV RNA increased and CD4 counts declined significantly, but NP performance did not change. Following reinitiation of HAART, viral loads fell below pre-TI levels, and CD4 counts rose. Improved viral suppression and immune restoration with reinitiation of HAART resulted in significant improvement in neurocognitive performance. No changes on comprehensive questionnaires of mood state were observed in relation to TI. NP performance and mood state remained stable during TIs despite worsened viral loads and CD4 counts. Because “practice effects” are generally greatest between the first and second NP testing sessions, improvement at the third, post-TI time point was unlikely to be accounted for by practice. TIs of up to 6 months appear to be neurocognitively and psychiatrically safe for most patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Beck A, Steer R, Brown G (1996). BDI-II Beck Depression Inventory manual. San Antonio, TX: Harcourt Brace and Company.
Benedict RH (1997). Brief Visuospatial Memory Test— Revised. Odessa, TX: Psychological Assessments Resources.
Benedict RH, Schretlen D, Groninger L, Brandt J (1998). Hopkins Verbal Learning Test—Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychologist 12: 43–55.
Benton A, Hamsher K, Sivan A (1994). Multilingual aphasia examination. Iowa City, IA: AJA Associates.
Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK (2004). Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26: 307–319.
CDC (1992). 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mort Wkly Rep 41: 1–19.
Chesney MA, Ickovics JR, Chambers DB, Gifford AL, Neidig J, Zwickl B, Wu AW (2000). Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG). AIDS Care 12: 255–266.
Childs EA, Lyles RH, Selnes OA, Chen B, Miller EN, Cohen BA, Becker JT, Mellors J, McArthur JC (1999). Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 52: 607–613.
Diehr MC, Heaton RK, Miller W, Grant I (1998). The Paced Auditory Serial Addition Task (PASAT): norms for age, education, and ethnicity. Assessment 5: 375–387.
Duff K, Westervelt HJ, McCaffrey RJ, Haase RF (2001). Practice effects, test-retest stability, and dual baseline assessments with the California Verbal Learning Test in an HIV sample. Arch Clin Neuropsychol 16: 461–476.
El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fatkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C (2006). CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355: 2283–2296.
Ellis RJ, Gamst AC, Capparelli E, Spector SA, Hsia K, Wolfson T, Abramson I, Grant I, McCutchan JA (2000). Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 54: 927–936.
Ellis RJ, Hsia K, Spector SA, Nelson JA, Heaton RK, Wallace MR, Abramson I, Atkinson JH, Grant I, McCutchan JA (1997). Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. Ann Neurol 42: 679–688.
Ellis RJ, Moore DJ, Childers ME, Letendre S, McCutchan JA, Wolfson T, Spector SA, Hsia K, Heaton RK, Grant I (2002). Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol 59: 923–928.
Gladsjo JA, Schuman CC, Evans JD, Peavy GM, Miller SW, Heaton RK (1999). Norms for letter and category fluency: demographic corrections for age, education, and ethnicity. Assessment 6: 147–178.
Golden C (1978). Stroop Color and Word test. Chicao, IL: Stoelting.
Gronwall DM (1977). Paced auditory serial-addition task: a measure of recovery from concussion. Percept Motor Skills 44: 367–373.
Gronwall DM, Sampson H (1974). The psychological effects of concussion. Auckland: Auckland University Press.
Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, McCutchan JA, Taylor MJ, Kelly MD, Ellis RJ, etal (1995). The HNRC 500—Neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1: 231–251.
Heaton RK, Grant I, Matthews CG (1991). Comprehensive norms for an expanded Halstead-Reitan Battery: demographic corrections, research findings, and clinical applications. Odessa, TX: Psychological Assessment Resources.
Heaton RK, Taylor MJ, Manly JJ (2002). Demographic effects and use of demographically corrected norms with the WAIS-III and WMS-III. In: Clinical interpretation of the WAIS-III and WMS-III. Ledbetter M (ed). San Diego: Academic Press.
Klove H (1963). Clinical neuropsychology. In: Medical clinics of North America. Forster F (ed). New York: Saunders.
Kongs S, Thompson L, Iverson G, Heaton RK (2000). Wisconsin Card Sorting Test—64 card computerized version. Odessa, TX: Psychological Assessment Resources.
Letendre S, Capparelli EV, Ellis RJ, McCutchan JA (2000). Indinavir population pharmacokinetics in plasma and cerebrospinal fluid. The HIV Neurobehavioral Research Center Group. Antimicrob Agents Chemother 44: 2173–2175.
Letendre S, Ellis R, Grant I, McCutchan A, the HNRC Group (2001). The CSF concentration (conc)/IC50 ratio: a predictor of CNS antiretroviral (ARV) efficacy. In: Eighth Conference on Retroviruses and Opportunistic Infections. Chicago, Feb 5–8, 2001 Abstract K1004p.
Marcotte TD, Deutsch R, McCutchan JA, Moore DJ, Letendre S, Ellis RJ, Wallace MR, Heaton RK, Grant I (2003). Prediction of incident neurocognitive impairment by plasma HIV RNA and CD4 levels early after HIV seroconversion. Arch Neurol 60: 1406–1412.
McNair D, Lorr M, Droppleman L (1992). Profile of Mood States (POMS) manual. San Diego: Educational and Industrial Testing Services.
Nyenhuis DL, Yamamoto C, Luchetta T, Terrien A, Parmentier A (1999). Adult and geriatric normative data and validation of the profile of mood states. J Clin Psychol 55: 79–86.
Price RW, Deeks SG (2004). Antiretroviral drug treatment interruption in human immunodeficiency virus-infected adults: clinical and pathogenetic implications for the central nervous system. J NeuroVirol 10(Suppl 1): 44–51.
Price RW, Yiannoutsos CT, Clifford DB, Zaborski L, Tselis A, Sidtis JJ, Cohen B, Hall CD, Erice A, Henry K (1999). Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS 13: 1677–1685.
Reddy YS, Kashuba A, Gerber J, Miller V (2003). Round-table report: importance of antiretroviral drug concentrations in sanctuary sites and viral reservoirs. AIDS Res Hum Retroviruses 19: 167–176.
Reitan R, Wolson D (1993). The Halstead-Reitan Neuropsychological Test Battery, 2nd ed. Tuscon, AZ: Neuropsychology Press.
Richardson JL, Martin EM, Jimenez N, Danley K, Cohen M, Carson VL, Sinclair B, Racenstein JM, Reed RA, Levine AM (2002). Neuropsychological functioning in a cohort of HIV infected women: importance of antiretroviral therapy. J Int Neuropsychol Soc 8: 781–793.
Ruiz L, Ribera E, Bonjoch A, Romeu J, Martinez-Picado J, Paredes R, Diaz M, Marfil S, Negredo E, Garcia-Prado J, Tural C, Sirera G, Clotet B (2003). Role of structured treatment interruption before a 5-drug salvage antire-troviral regimen: the Retrogene Study. J Infect Dis 188: 977–985.
Sattler JM (2001). Assessment of children: cognitive applications, 4th ed. La Mesa, CA: Jerome M. Sattler.
Taylor S, Boffito M, Khoo S, Smit E, Back D (2007). Stopping antiretroviral therapy. AIDS 21: 1673–1682.
The Psychological Corporation (ed). (1997). Wechsler Adult Intelligence Scale—Third Edition (WAIS-III). San Antonio, TX: The Psychological Corporation.
Touloumi G, Pantazis N, Antoniou A, Stirnadel HA, Walker SA, Porter K (2006). Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. J Acquir Immune Defic Syndr 42: 554–561.
Tozzi V, Balestra P, Galgani SP, Narciso P, Ferri F, Sebastiani G, Amato CC, Affricano C, Pigorini F, Pau F, De Felici A, Benedetto A (1999). Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment. AIDS 13: 1889–1897.
United States Army (1994). Army Individual Test Battery—manual of directions and scoring. Washington, DC: War Department, Adjutant General’s Office.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
The San Diego HIV Neurobehavioral Research Center Group (Letendre et al, 2000, Antimicrob Agents Chemother 44: 2173–2175) is affiliated with the University of California, San Diego, the Naval Hospital, San Diego, and the San Diego Veterans Affairs Healthcare System, and includes Director: Igor Grant, MD; Co-Directors: J. Hampton Atkinson, MD, and J. Allen McCutchan, MD; Center Manager: Thomas D. Marcotte, PhD; Naval Hospital San Diego: Mark R. Wallace, MD (P.I.); Neuromedical Component: J. Allen McCutchan, MD (P.I.), Ronald J. Ellis, MD, Scott Letendre, MD, Rachel Schrier, PhD; Neurobehavioral Component: Robert K. Heaton, PhD (P.I.), Mariana Cherner, PhD, Julie Rippeth, PhD, Joseph Sadek, PhD, Steven Paul Woods, PsyD; Imaging Component: Terry Jernigan, PhD (P.I.), John Hesselink, MD, Michael J. Taylor, PhD; Neuropathology Component: Eliezer Masliah, MD (P.I.), Dianne Langford, PhD; Clinical Trials Component: J. Allen McCutchan, MD, J. Hampton Atkinson, MD, Ronald J. Ellis, MD, PhD, Scott Letendre, MD; Data Management Unit: Daniel R. Masys, MD (P.I.), Michelle Frybarger, BA(Data Systems Manager); Statistics Unit: Ian Abramson, PhD (P.I.), Reena Deutsch, PhD, Deborah Lazzaretto, M.A.
The HIV Neurobehavioral Research Center is supported by Center award 5 P30 MH62512-01 from the National Institutes of Mental Health (NIMH). Dr. R. J.Ellis is supported by R01 MH58076.
Rights and permissions
About this article
Cite this article
Childers, M.E., Woods, S.P., Letendre, S. et al. Cognitive functioning during highly active antiretroviral therapy interruption in human immunodeficiency virus type 1 infection. Journal of NeuroVirology 14, 550–557 (2008). https://doi.org/10.1080/13550280802372313
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1080/13550280802372313