Citation: Ellis RJ (2007) Evidence-Based Treatment for HIV-Associated Dementia and Cognitive Impairment: Why So Little. PLOS Clin Trial 2(3): e15. https://doi.org/10.1371/journal.pctr.0020015
Published: March 30, 2007
Copyright: © 2007 Ronald J. Ellis. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Dr. Ellis is supported by United States National Institutes of Health grant R01 MH 58076 and N01 MH 22005. No specific funding was received for writing this piece.
Competing interests: The author has declared that no competing interests exist.
Abbreviations: ART, antiretroviral therapy; central nervous system(CNS) CNS, central nervous system; HAART, highly active antiretroviral therapy; HAD, HIV-associated dementia; SBG, stable background therapy
The Abacavir Trial in Context
HIV-associated dementia (HAD) and milder forms of cognitive impairment produce a spectrum of disability that ranges from complete inability to care for oneself to reduced work efficiency and quality of life. HAD is believed to arise from a confluence of adverse effects on neuronal function resulting both from HIV itself and from disturbances in cellular signalling, particularly in the immune system, that further damage neurons. More than two decades after the recognition of HAD as a clinical entity, guidelines for antiretroviral drug treatment in people with HAD and cognitive impairment have yet to be established. The study reported in PLoS Clinical Trials by Brew et al.  was designed to help develop such guidelines by testing whether adding a single “neuroactive” antiretroviral, abacavir, to an existing regimen would benefit brain function in patients with dementia. Abacavir is a potent inhibitor of HIV reverse transcriptase that interferes with the viral lifecycle and shows reasonably good penetration into central nervous system (CNS) tissues. The trial was historically important because it was done at a pivotal time in the development of antiretroviral therapy, as potent combination drug regimens including protease inhibitors emerged into widespread use in the United States, Europe, and Australia.
The rationale for the study was simple and transparent. It was anticipated that this “CNS active” agent would suppress a potential reservoir of HIV in the central nervous system, where other drugs, especially protease inhibitors, might not be effective. At the time this study was designed, a number of important scientific observations about HAD and its treatment had been made. Zidovudine, the earliest available nucleoside reverse transcriptase inhibitor, seemed to improve the motor functions of people with HAD when given in higher doses than normally used for treatment of systemic HIV disease . Additionally, observational data showed that dementia prevalence in the West dropped after zidovudine became available, suggesting that zidovudine prevented HAD [3,4]. Even so, the burden of mild cognitive impairment in HIV remained substantial [5–7].The trial was historically important because it was done at a pivotal time in the development of antiretroviral therapy.
What Has Been Learnt Since This Trial Was Conducted?
Although the trial reported here  was completed in January 1998, publication was delayed for several years. In the years between completion and publication of the trial, knowledge about the impact of antiretroviral therapy on cognitive impairment in HIV continued to accumulate. New cases of severe dementia became less frequent [8,9], and there was clear evidence of improved cognitive function, even in those with mild impairment . Immunity improved and longevity increased in surviving patients with dementia and mild cognitive impairment. This increase in survival was particularly dramatic for individuals with frank dementia: in the era before highly active antiretroviral therapy (HAART), average survival was about five months, whereas in the HAART era it is close to 40 months . However, many affected individuals did not fully recover their baseline cognitive abilities. Thus, the prevalence of cognitive impairment gradually increased  and it became more common in persons with higher CD4 counts [12,13]. Finally, evidence emerged, albeit not unanimous, that cognitive recovery was greatest in those who received antiretroviral medications with better CNS penetration characteristics and in those who fully suppressed viral load in cerebrospinal fluid .
Findings of the Abacavir Trial
In this randomized, double-blind, placebo-controlled trial, 105 HIV-positive patients with HAD who were already receiving combination antiretroviral regimens (“stable background therapy” [SBG]) for at least eight weeks were randomized to treatment with abacavir or placebo for 12 weeks, in addition to their existing regimen. Patients in both treatment arms improved substantially, with the median change in a composite neuropsychological performance index (NPZ) at week 12 exceeding one half of a standard deviation. Improvement was slightly, but not statistically significantly better in the abacavir-treated patients than in those receiving placebo.
Interpretation, Strengths, and Limitations
A strength of this study is that it is one of very few prospective, randomized, blinded comparative trials for HAD. The study was well-designed and the agent, a newly developed, potent, nucleoside reverse transcriptase inhibitor with favorable pharmacological and tolerability characteristics and predicted good CNS penetration, was of great interest. The targeted patient group was clearly defined and had received relatively little attention in prior antiretroviral treatment studies, offering the potential for this study to have a substantial impact on prescribing practices. However, the study's ability to fulfill its goals was substantially limited by several factors, including rapid new developments in antiviral treatment for HIV.
First, although referred to as “optimal” background therapy, participants' regimens at trial entry were for the most part failing, with virologic success (undetectable plasma viral load) having been achieved in only 23% of individuals in the abacavir arm, and 9% of individuals in the placebo arm. This lack of virologic efficacy of SBG may have reflected a variety of contributing factors, including drug resistance, poor adherence to ART resulting from cognitive impairment, and the relative inexperience of practitioners at that time in applying combination regimens. Additionally, since access to abacavir was restricted at the time the study was being performed, it is possible—even likely—that referral of patients to this study was biased towards those who were failing their existing regimens and therefore in need of a new agent.
Second, although the investigators could not have known it at the time, single agent add-on therapy was subsequently shown to be largely ineffective. Antiretroviral treatment guidelines released after the trial began clearly indicate that, for ART-treated individuals with emerging virologic failure (detectable plasma viral load) and suspected drug resistance, providers should change at least two drugs in the regimen to active agents . Thus the main intervention of this study, adding a single agent to an existing, failing antiretroviral regimen, was in retrospect not a viable treatment strategy.
Virologic suppression from baseline to 12 weeks improved somewhat more in the abacavir group (23% to 46%) than in the placebo arm (9% to 13%). Brew et al.  interpret this as demonstration of the virologic efficacy of abacavir add-on therapy. However, the median baseline viral load for the abacavir group (3.7 log10 c/ml) was substantially closer to the assay detection limit (2.6 log10 c/ml) than for the placebo group (4.6 log10 c/ml). By way of contrast, effective, modern combination regimens achieve virologic suppression in more than two thirds of patients over 12 weeks, and frequently produce viral load declines of 2–3 logs . Additional evidence of the limited potency of abacavir versus placebo was provided by the lack of CD4 response in both groups. Individuals with CD4 counts comparable to those in this study frequently show substantial CD4 benefit with effective ART. Since abacavir had a very modest effect on the virus, and virtually none on immunity, its effects on brain function may have been so modest as to elude detection by neuropsychological testing.The abacavir trial has taught us several important lessons.
This issue is of particular importance since most of the individuals in this study had mild or moderate, rather than severe cognitive impairment. While the clinical significance of mild cognitive impairment is clear in relation to Alzheimer disease, where early intervention may prevent or delay the onset of frank dementia, its relationship to dementia in HIV-positive patients is less clear. In HIV, mild cognitive impairment does not predictably progress to dementia. Therefore, to demonstrate efficacy, therapies need to be more potent, more patients need to be studied, or both.
One possible explanation for the lack of difference between the abacavir and placebo patients is that there was a large practice effect in both groups; that is, patients took the same tests repeatedly, giving them the opportunity to better their performance with practice, independent of any improvement in brain function. If practice effects were large in both treatment groups, their magnitude might have obscured any incremental improvement related to the hypothesized beneficial effect of abacavir on brain function. Brew et al.  argue that this explanation is unlikely. However, the fact that the tests were administered twice (baseline, week 6) before the time point at which the primary outcome was measured (week 12) gave participants ample opportunity to benefit from practice. Other clinical trials with a similar design have also found substantial improvements within individuals randomized to the placebo arm over the course of the trial .
Another potential reason for the lack of superiority of abacavir was that patients in both groups were continuing to experience improvement related to their initial ART (SBG), independent of the study intervention. Similar to practice effects, the argument here is that the magnitude of this improvement in all subjects related to SBG overwhelmed any additional incremental benefit related to abacavir itself. However, if both groups were still benefiting substantially from the introduction of their prior antiretroviral regimens, then it should have been possible to demonstrate a graded effect, with improvements being greatest in those who started their background regimens more recently and least in those whose background regimens had been started more remotely. Unfortunately, information about the duration of therapy prior to study enrollment is not provided in the article, so this possibility cannot be adequately evaluated.
Implications for Clinical Practice, Research, Health Policy, and the Future of HIV Neurotherapeutics
The abacavir trial has taught us several important lessons. First, since potent, combination systemic ART is available it is no longer acceptable to design trials of single antiretroviral agents. Instead, we need to design trials using combination antiretroviral therapies, and clinical trialists need to anticipate emerging developments in ART and plan for their impact. We need to improve the sensitivity and specificity of methods for measuring neurocognitive change over time. For example, the Reliable Change Index represents a methodologically rigorous means of identifying meaningful neuropsychological performance improvement in individual participants . Scores above a statistically specified confidence interval are interpreted as improvement beyond what would be expected based on normal variability and practice effects. We need to better understand the natural history and interrelationships of dementia and milder forms of neurocognitive impairment. Finally, clinically useful predictive and surrogate markers might help to conduct controlled clinical trials rapidly, and with large enough numbers to impact practice.
- 1. Brew BJ, Halman M, Catalan J, Sacktor N, Price RW, et al. (2006) Factors in AIDS dementia complex trial design: Results and lessons from the abacavir trial. PLoS Clin Trials. 2. BJ BrewM. HalmanJ. CatalanN. SacktorRW Price2006Factors in AIDS dementia complex trial design: Results and lessons from the abacavir trial.PLoS Clin Trials2e13.
- 2. Sidtis JJ, Gatsonis C, Price RW, Singer EJ, Collier AC, et al. (1993) Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial. AIDS Clinical Trials Group. Ann Neurol 33: 343–349.JJ SidtisC. GatsonisRW PriceEJ SingerAC Collier1993Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial. AIDS Clinical Trials Group.Ann Neurol33343349
- 3. Portegies P, Enting RH, de Gans J, Algra PR, Derix MM, et al. (1993) Presentation and course of AIDS dementia complex: 10 years of follow-up in Amsterdam, The Netherlands. AIDS 7: 669–675.P. PortegiesRH EntingJ. de GansPR AlgraMM Derix1993Presentation and course of AIDS dementia complex: 10 years of follow-up in Amsterdam, The Netherlands.AIDS7669675
- 4. Gray F, Geny C, Dournon E, Fenelon F, Lionnet F, et al. (1991) Neuropathological evidence that zidovudine reduces incidence of HIV infection of brain. Lancet 337: 852–853.F. GrayC. GenyE. DournonF. FenelonF. Lionnet1991Neuropathological evidence that zidovudine reduces incidence of HIV infection of brain.Lancet337852853
- 5. Heaton RK, Grant I, Butters N, White DA, Kirson D, et al. (1995) The HNRC 500—Neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1: 231–251.RK HeatonI. GrantN. ButtersDA WhiteD. Kirson1995The HNRC 500—Neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center.J Int Neuropsychol Soc1231251
- 6. Stern Y, Liu X, Marder K, Todak G, Sano M, et al. (1995) Neuropsychological changes in a prospectively followed cohort of homosexual and bisexual men with and without HIV infection. Neurology 45: 467–472.Y. SternX. LiuK. MarderG. TodakM. Sano1995Neuropsychological changes in a prospectively followed cohort of homosexual and bisexual men with and without HIV infection.Neurology45467472
- 7. Ellis RJ, Deutsch R, Heaton RK, Marcotte TD, McCutchan JA, et al. (1997) Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group. Arch Neurol 54: 416–424.RJ EllisR. DeutschRK HeatonTD MarcotteJA McCutchan1997Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group.Arch Neurol54416424
- 8. Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, et al. (1999) Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 13: 1249–1253.GJ DorePK CorrellY. LiJM KaldorDA Cooper1999Changes to AIDS dementia complex in the era of highly active antiretroviral therapy.AIDS1312491253
- 9. Maschke M, Kastrup O, Esser S, Ross B, Hengge U, et al. (2000) Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry 69: 376–380.M. MaschkeO. KastrupS. EsserB. RossU. Hengge2000Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART).J Neurol Neurosurg Psychiatry69376380
- 10. Ferrando SJ, Rabkin JG, van Gorp W, Lin SH, McElhiney M (2003) Longitudinal improvement in psychomotor processing speed is associated with potent combination antiretroviral therapy in HIV-1 infection. J Neuropsychiatry Clin Neurosci 15: 208–214.SJ FerrandoJG RabkinW. van GorpSH LinM. McElhiney2003Longitudinal improvement in psychomotor processing speed is associated with potent combination antiretroviral therapy in HIV-1 infection.J Neuropsychiatry Clin Neurosci15208214
- 11. Dore GJ, McDonald A, Li Y, Kaldor JM, Brew BJ (2003) Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 17: 1539–1545.GJ DoreA. McDonaldY. LiJM KaldorBJ Brew2003Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy.AIDS1715391545
- 12. Tozzi V, Balestra P, Lorenzini P, Bellagamba R, Galgani S, et al. (2005) Prevalence and risk factors for human immunodeficiency virus-associated neurocognitive impairment, 1996 to 2002: Results from an urban observational cohort. J Neurovirol 11: 265–273.V. TozziP. BalestraP. LorenziniR. BellagambaS. Galgani2005Prevalence and risk factors for human immunodeficiency virus-associated neurocognitive impairment, 1996 to 2002: Results from an urban observational cohort.J Neurovirol11265273
- 13. Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, et al. (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8: 136–142.N. SacktorMP McDermottK. MarderG. SchifittoOA Selnes2002HIV-associated cognitive impairment before and after the advent of combination therapy.J Neurovirol8136142
- 14. Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, et al. (2004) Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol 56: 416–423.SL LetendreJA McCutchanME ChildersSP WoodsD. Lazzaretto2004Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders.Ann Neurol56416423
- 15. United States Department of Health and Human Services (2006) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. United States Department of Health and Human Services2006Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescentsAvailable: http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. Accessed 20 February 2007. Available: http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. Accessed 20 February 2007.
- 16. Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, et al. (2006) Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society—USA panel. Top HIV Med 14: 827–843.SM HammerMS SaagM. SchechterJS MontanerRT Schooley2006Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society—USA panel.Top HIV Med14827843
- 17. Schifitto G, Navia BA, Yiannoutsos CT, Marra CM, Chang L, et al. (2007) Memantine and HIV-associated cognitive impairment: A neuropsychological and proton magnetic resonance spectroscopy study. AIDS. G. SchifittoBA NaviaCT YiannoutsosCM MarraL. Chang2007Memantine and HIV-associated cognitive impairment: A neuropsychological and proton magnetic resonance spectroscopy study.AIDSIn press. In press.
- 18. Woods SP, Childers M, Ellis RJ, Guaman S, Grant I, et al. (2006) A battery approach for measuring neuropsychological change. Arch Clin Neuropsychol 21: 83–89.SP WoodsM. ChildersRJ EllisS. GuamanI. Grant2006A battery approach for measuring neuropsychological change.Arch Clin Neuropsychol218389