Cognitive neurorehabilitation of HAND: Have we forgotten something?
The introduction of combination antiretroviral therapy (cART) in the late 1990s dramatically changed the landscape of HIV infection in the U.S. by reducing mortality rates and increasing health-related quality of life (e.g., Hogg et al., 1998). Despite such pharmacological advancements in the treatment of virologic aspects of HIV infection, HIV-associated neurocognitive disorders (HAND) remain highly prevalent in the cART era (Heaton et al., 2010). While more severe forms of HAND (e.g., HIV-associated dementia) are now less common, the rates of milder subtypes of HAND may have actually increased in the cART era, especially amongst persons with otherwise well-managed disease (Heaton et al., 2011). It is estimated that approximately 40 to 50 percent of HIV-infected individuals experience HAND (Heaton et al., 2010), which is primarily marked by mild-to-moderate deficits in executive functions (e.g., planning, complex attention) and memory (i.e., acquisition and retrieval), along with impairments in psychomotor speed and working memory (Heaton et al., 2011). Such deficits have significant consequences for important aspects of everyday functioning, particularly medication adherence (e.g., Heaton et al., 2004), which leaves patients vulnerable to poorer disease outcomes and virologic breakthrough (e.g., Hogg et al., 2002).
In contrast to the remarkable advances in clinical management of immunological aspects of HIV, the armamentarium for effective management of HAND remains relatively barren. Pharmacological research on interventions for HAND has identified two potential candidates: antiretroviral therapy (ART) and non-ART medications. In general, the initiation of combination ART (cART) has been associated with improvements in neurocognition (Joska et al., 2010), especially in ART-naïve individuals (e.g., Letendre et al., 2004). Beyond this first line of standard-of-care cART, it may be possible to prescribe ART regimens that better penetrate the central nervous system (CNS), thereby more effectively controlling the direct and indirect effects of HIV replication on neural structure and function. While cross-sectional evidence exists to suggest that higher CNS penetrating regimens are associated with better neuropsychological outcomes (e.g., Letendre et al., 2008, Smurzynski et al., 2011), randomized controlled trials of the efficacy of CNS penetrating ART regimens on HAND are presently underway and are needed to support an evidence-based practice recommendation. Clinical research on non-ART medications for HAND has produced mixed results on neurocognitive outcomes. For instance, a single-arm study with lithium showed some neurocognitive improvement among participants (Letendre et al., 2006); this same group also found an association between use of serotonin reuptake inhibitors and neuropsychological outcomes (Letendre et al., 2007). Other non-ARV medications that have shown promise in this regard in pilot trials (e.g., selegiline, memantine) have not held up in larger, more rigorous trials (Sacktor et al., 2000; Schifitto et al., 2007, respectively).
Considering the limited success of pharmacological interventions, recent efforts have focused on adapting cognitive neurorehabilitation approaches to remediate HAND, but have thus far been limited in quantity and scope. Only one study, performed in a population of HIV-infected children in Uganda (Boivin et al., 2010), has examined the effectiveness of a memory- and attention-based cognitive rehabilitation training program (i.e., Captain's Log CCRT), which produced moderate improvements on measures of simple attention and information processing speed. To date, there are no published empirical studies of cognitive rehabilitation of HAND in adults, although there are a handful of ongoing trials being funded at the federal level.
However, some promise lies within the applied cognitive psychology and rehabilitation literature, in which a few studies have identified targeted techniques that may have potential for remediating HAND. An early study (Neundorfer et al., 2004) used spaced retrieval, a common technique in the rehabilitation literature that uses successive approximation to extend an individual’s recall abilities for specific information over time (e.g., Schacter et al., 1985). Spaced-retrieval demonstrated some efficacy in improving self-reported memory performance in HIV when used in conjunction with external compensatory strategies, such as a pillbox (Neundorfer et al., 2004). A more recent study demonstrated the effectiveness of a self-generation intervention in HIV (Weber, Woods, Kellogg et al., in press), whereby participants are presented with word pairs in either a didactic format (i.e., explicitly presented) or a self-generated condition, which is theorized to facilitate memory recall by deepening encoding of the information to be remembered. Using a paired-associates task, Weber and colleagues demonstrated a large effect size for self-generation in improving HIV-associated deficits in verbal memory (Weber, Woods, Kellogg et al., 2012). Clinically, this tool might be utilized by encouraging patients to self-generate aspects of their treatment that they will need to remember (e.g., appointment times, treatment goals). Spontaneous deployment of compensatory strategies in the laboratory has also been implicated in better working memory performance in older HIV-infected adults (Woods et al., 2010), potentially speaking to the additional importance of meta-cognition and insight in rehabilitation of neurocognition. Furthermore, older HIV+ adults who reported using compensatory memory strategies in their daily lives were more likely to remember to perform a task outside of the laboratory (Weber, Woods, Delano-Wood et al., in press), suggesting that these individuals may be adept at utilizing techniques to aid them on a day-to-day basis. Technologically-based compensatory strategies (e.g., cell phone texting) have also been effective in improving medication adherence in individuals with memory impairment (Andrade et al., 2004).
As we look toward the future of remediating HAND, it may be prudent to take cues from the cognitive rehabilitation literature for disorders with similar neurocognitive profiles in order to glean candidate therapies for the HIV-infected population (see Rohling et al., 2009). The majority of cognitive rehabilitation work has been done in the context of traumatic brain injury (TBI), as well as other neurological (e.g., stroke, multiple sclerosis) and psychiatric (e.g., schizophrenia) disorders, mostly in the domains of memory, executive functions and attention. Formal broad-based cognitive strategy training, in which individuals are instructed with basic strategies (e.g., using a day planner) to compensate for impaired neurocognition has been effective across a variety of populations (e.g., TBI, psychotic disorders), resulting in improved quality of life and other functional outcomes (e.g., Huckans et al., 2010; Twamley et al., 2008, respectively). Goal management training (GMT), for example, specifically targets executive dysfunction, a neurocognitive domain frequently impaired in the setting of HIV infection (Heaton et al., 2011) and often implicated in everyday functioning disability. GMT is designed to aid individuals in executing their intended goals using techniques like monitoring the environment and detailing subgoals to be completed (Robertson et al., 1996). This intervention has been effective in numerous populations, including TBI (e.g., Levine et al., 2000), frontal lobe dysfunction (e.g., Levine et al., 2011), and older adults (e.g., Stuss et al., 2007). Relatedly, the framework of this intervention overlaps onto the executive aspects of prospective memory, which are impaired in HIV infection (Carey et al., 2004) and are uniquely associated with poorer everyday functioning (e.g., medication nonadherence; Woods et al., 2009). Content-free cueing interventions have been used to improve prospective memory in the context of TBI (Fish et al., 2007) as a means to support deficient self-monitoring and use external means to encourage disengagement from ongoing tasks and the review of intended goals. In sum, while great strides have been made to characterize HAND and its everyday functioning impact over the past 25 years, we have only just begun the process of developing effective cognitive neurorehabilitation therapies that may inform evidence-based practice. Designing and validating such interventions for use in persons living with HIV infection will be an essential part of our efforts to improve our patients’ quality of life and health outcomes.
About the author
Steven P. Woods, PsyD, is an associate professor of psychiatry at UC San Diego. He received a BS in psychology from Portland State University in Portland, Oregon. In 2000, he earned a PsyD in clinical psychology with a specialization in neuropsychology from the Virginia Consortium Program in Clinical Psychology (The College of William & Mary, Eastern Virginia Medical School, Norfolk State University, and Old Dominion University). He completed a predoctoral internship at the VA Connecticut Healthcare System and a postdoctoral residency in clinical neuropsychology at the University of Washington. His primary research interests lie in the application of cognitive models (e.g., prospective memory) to examine the everyday functioning impact (e.g., medication adherence) of HIV infection and substance use disorders. He was the recipient of the 2007 Early Career Award for Contributions to Clinical Neuropsychology from the National Academy of Neuropsychology and the 2008 Robert A. and Phyllis Levitt Early Career Award in Neuropsychology from the American Psychological Association (Division 40).
Erica Weber, MA, is currently in her third year of the SDSU/UCSD Joint Doctoral Program in Clinical Neuropsychology, studying under the mentorship of Dr. Steven Paul Woods at the UCSD HIV Neurobehavioral Research Programs. Prior to her arrival in San Diego, she received her BA in psychology with a minor in applied statistics from Boston University in 2005. Her primary research focuses include the neuropsychology of HIV and substance dependence and their respective impacts on indices of daily functioning (e.g., employment). Additionally, she is interested in the use of cognitive models to inform rehabilitation of memory deficits in neurological and addictions populations.
Andrade, A.S., McGruder, H.F., Wu, A.W., Celano, S.A., Skolasky, R.L. Jr, Selnes, O.A., ... McArthur, J.C. (2005). A programmable prompting device improves adherence to highly antiretroviral therapy in HIV-infected subjects with memory impairment, Clinical Infectious Diseases, 41, 875-882.
Boivin, M.J., Busman, R.A., Parikh, S.M., Bangirana, P., Page, C.F., Opoka, R.O., & Giordani, B. (2010). A pilot study of the neuropsychological benefits of computerized cognitive rehabilitation in Ugandan children with HIV, Neuropsychology, 24, 667-673.
Carey, C.L., Woods, S.P., Rippeth, J.D., Heaton, R.K., Grant, I., & The HNRC Group. (2004). Prospective memory in HIV-1 infection, Journal of Clinical and Experimental Neuropsychology, 28, 536-548.
Fish, J., Evans, J.J., Nimmo, M., Martin, E., Kersel, D., Bateman, A., ... Manly, T. (2007). Rehabilitation of executive dysfunction following brain injury: “Content-free” cueing improves everyday prospective memory performance, Neuropsychologia, 45, 1318-1330.
Heaton, R. K., Clifford, D. B., Franklin, D. R., Woods, S. P., Ake, C., Vaida, F., ... The CHARTER Group. (2010). HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study, Neurology, 75, 2087-2096.
Heaton, R. K., Franklin, D. R., Ellis, R. J., McCutchan, J. A., Letendre, S. L., Leblanc, S., … The HNRC Group. (2011). HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: Differences in rates, nature, and predictors, Journal of Neurovirology, 17, 3-16.
Heaton, R.K., Marcotte, T.D., Mindt, M.R., Sadek, J., Moore, D.J., Bentley, H., … The HNRC Group. (2004). The impact of HIV-associated neuropsychological impairment on everyday functioning, Journal of the International Neuropsychological Society, 10, 317-331.
Hogg, R.S., Heath, K., Bangsberg, D., Yip, B., Press, N., O’Shaughnessy, M.V., & Montaner, J.S. (2002). Intermittent use of triple-combination therapy is predictive of mortality at baseline and after one year of follow-up, AIDS, 16, 1051-1058.
Hogg, R.S., Heath, K.V., Yip, B., Craib, K.J., O'Shaughnessy, M.V., Schechter, M.T., Montaner, J.S. (1998) Improved survival among HIV-infected individuals following initiation of antiretroviral therapy, JAMA, 279, 450-454.
Huckans, M., Pavawalla, S., Demadura, T., Kolessar, M., Seelye, A., Roost, N., … Storzbach, D. (2010). A pilot study examining the effects of group-based Cognitive Strategy Training treatment on self-reported cognitive problems, psychiatric problems, functioning, and compensatory strategy use in OIF/OEF combat veterans with persistant mild cognitive disorder and history of traumatic brain injury, Journal of Rehabilitation Research and Development, 47, 43-60.
Joska, J.A., Gouse, H., Paul, R.H., Stein, D.J., & Flisher, A.J. (2010). Does highly active antiretroviral therapy improve neurocognitive function? A systematic review, Journal of Neurovirology, 16, 101-114.
Letendre, S.L., Marquie-Beck, J., Capparelli, E., Best, B., Clifford, D., Collier, A.C., … The CHARTER Group. (2008). Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system, Archives of Neurology, 65, 65-70.
Letendre, S.L., Marquie-Beck, J., Ellis, R.J., Woods, S.P., Best, B., Clifford, D.B., … The CHARTER Group (2007). The role of cohort studies in drug development: clinical evidence of antiviral activity of serotonin reuptake inhibitors and HMG-CoA reductase inhibitors in the central nervous system, Journal of Neuroimmune Pharmacology, 2, 120–127.
Letendre, S.L., McCutchan, J.A., Childers, M.E., Woods, S.P., Lazzaretto, D., … The HNRC Group (2004). Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders, Annals of Neurology, 56, 416-423.
Letendre, S.L., Woods, S.P., Ellis, R.J., Atkinson, J.H., Masliah, E., van den Brande, G., … HNRC Group. (2006). Lithium improves HIV-associated neurocognitive impairment, AIDS, 20, 1885–1888.
Levine, B., Robertson, I.H., Clare, L., Carter, G., Hong, J., Wilson, B.A., … 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.
Levine, B., Schweizer, T.A., O’Connor, C., Turner, G., Gillingham, S., Stuss, D.T., … Robertson, I.H. (2011). Rehabilitation of executive functioning in patient with frontal lobe brain damage with goal management training, Frontiers in Human Neuroscience, 17, 5:9.
Neundorfer, M.M., Camp, C.J., Lee, M.M., Skrajner, M.J., Malone, M.L., & Carr, J.R. (2004). Compensating for cognitive deficits in person aged 50 and over with HIV/AIDS: A pilot study of a cognitive intervention, Journal of HIV/AIDS & Social Services, 3, 79–97.
Robertson, I.H. (1996). Goal management training: A clinical manual. Cambridge, UH: PsyConsult.
Rohling, M.L., Faust, M.E., Beverly, B., & Demakis, G. (2009). Effectiveness of cognitive rehabilitation following acquired brain injury: A meta-analytic re-examination of Cicerone et al.’s (2000, 2005) systematic reviews, Neuropsychology, 23, 20-39.
Sacktor, N., Schifitto, G., McDermott, M.P., Marder, K., McArthur, J.C., & Kieburtz, K. (2000). Transdermal selegiline in HIV-associated cognitive impairment: Pilot, placebo-controlled study, Neurology, 54, 233-235.
Schacter, D.L., Rich, S.A., & Stampp, M.S. (1985). Remediation of memory disorders: Experimental evaluation of the spaced-retrieval technique, Journal of Clinical and Experimental Neuropsychology, 7, 79-96.
Schifitto, G., Navia, B.A., Yiannoutsos, C.T., Marra, C.M., Chang, L., Ernst, T., … HIV MRS Consortium. (2007). Memantine and HIV-associated cognitive impairment: A neuropsychological and proton magnetic resonance spectroscopy study, AIDS, 21, 1877-1886.
Smurzynski, M., Wu, K., Letendre, S., Robertson, K., Bosch, R.J., Clifford, D.B., … Ellis R. (2011). Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort, AIDS, 25, 357-365.
Stuss, D.T., Robertson, I.H., Craik, F.I., Levine, B., Alexander, M.P., Black, S., … Winocur, G. (2007). Cognitive rehabilitation in the elderly: A randomized trial to evaluate a new protocol, Journal of the International Neuropsychological Society, 13, 120-131.
Twamley, E.W., Savla, G.N., Zurhellen, C.H., Heaton, R.K., & Jeste, D.V. (2008). Development and pilot testing of a novel compensatory cognitive training intervention for people with psychosis, American Journal of Psychiatric Rehabilitation, 11, 144-163.
Weber, E., Woods, S.P., Delano-Wood, L., Bondi, M.W., Gilbert, P.E., Grant, I., & The HNRP Group. (2011). An examination of the age-prospective memory paradox in HIV-infected adults, Journal of Clinical and Experimental Neuropsychology, 33(10), 1108-18.
Weber, E., Woods, S.P., Kellogg, E., Grant, I., Basso, M., & The HNRP Group. (2012). Self-generation enhances verbal recall in individuals infected with HIV, Journal of the International Neuropsychological Society, 18(1), 128-133.
Woods, S.P., Dawson, M.S., Weber, E., Gibson, S.A., Letendre, S.L., Grant, I., & The HNRC Group. (2009). Timing is everything: Antiretroviral non-adherence is associated with impairment in time-based prospective memory, Journal of the International Neuropsychological Society, 15, 42-52.
Woods, S.P., Weber, E., Cameron, M.V., Dawson, M.S., Grant, I., & The HNRC Group. (2010). Spontaneous strategy use protects against visual working memory deficits in older adults infected with HIV, Archives of Clinical Neuropsychology, 25, 724-733.