The use of HAART has significantly improved the survival of HIV-infected subjects [1–3], as well as neurocognitive functioning in some individuals [4–6]. However, because many antiretroviral agents, particularly protease inhibitors, generally penetrate poorly across the blood–brain barrier, a significant number of HIV-infected individuals may remain vulnerable to neurological injury and be at risk for developing cognitive impairment despite adequate plasma suppression of HIV RNA concentration. In fact, emerging evidence suggests that cognitive impairment and brain abnormalities may unfold or persist in the setting of HAART and partial immune reconstitution [7–10]. Together, these observations indicate a need to identify safe and effective adjuvant therapies that can either restore or prevent further loss of neurologic function in the setting of stable systemic disease.
In vitro studies have shown that memantine (1-amino-3,5 dimethyl-adamantane) can prevent the neurotoxicity of gp120, Tat, and PAF, and reduce neuronal injury and loss in the gp120 transgenic mouse [11–13]. In addition, Gendelman and colleagues have shown in a murine model of HIV encephalitis that memantine significantly attenuates the damaging effects of HIV infection on synaptic transmission in the hippocampus and long term potentiation, widely believed to be a critical neurophysiological substrate for learning and memory .
Memantine, an analog of the antiviral drug amantadine, acts as an uncompetitive/fast off rate, low affinity (micromolar range) antagonist of the N-methyl-D-aspartate (NMDA) receptor [15,16]. It has been widely used in Europe for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease [17–20], and more recently has received FDA approval for the treatment of AD [21,22].
We conducted a double-blind, placebo-controlled study of memantine within the Adult AIDS Clinical Trial Group (AACTG) to assess its safety and efficacy in subjects with AIDS Dementia Complex (ADC). To further assess the in vivo effects of memantine, proton magnetic resonance spectroscopy (MRS) was performed in a subgroup of subjects. MRS provides a noninvasive and reliable method to assess brain injury in HIV infection by measuring metabolites associated with glia and neuronal cell function [7,23–35].
One hundred forty subjects with a diagnosis of ADC stage 1 or greater and neuropsychological impairment were randomized via a central computer system (www.fstrf.org) at 21 AACTG centers between February 1997 and December 1999. Neuropsychological impairment was defined as: at least two standard deviations below the normative value on one or more neuropsychological tests, or one standard deviation below the normative on at least two tests. Subjects were required to be on stable antiretroviral therapy for 6 weeks prior to entry and to maintain this regimen during the course of the study. Subjects with a history of focal brain lesions, chronic seizures, active psychiatric disorders, or active alcohol or drug abuse were excluded. Subjects receiving a stable antidepressant regimen were not excluded from participation.
At entry, subjects were stratified according to two factors: zidovudine (ZDV) use (current use, previous use, or no use), and ADC stage. The protocol underwent review and approval by the Institutional Review Boards at all participating sites. Informed consent was obtained from all subjects or their authorized representatives.
This was a randomized, double-blind, placebo-controlled, phase II study. Memantine dose was initiated at 10 mg per day during the first study week and was escalated by 10 mg in weekly increments to 40 mg per day by week 4, or up to the maximum tolerated dose. Memantine administration was continued to week 16 (the primary evaluation visit), followed by a 4-week drug washout period and re-evaluation at week 20. Similarly, the placebo dose started at one pill per day and escalated by one pill in weekly increments to four pills per day or to the maximum tolerated dose.
Toxicities were graded as: 1, mild not requiring treatment; 2, moderate requiring treatment; 3, severe; and 4, potentially life threatening.
Neurological and neuropsychological studies
Neurologic assessments were performed at baseline, weeks 4, 8, 12, 16 and, following the 4-week washout period, at week 20. ADC stage was assessed according to the Memorial-Sloan Kettering Classification  at the same weekly visits. Neuropsychological assessments were performed at baseline and weeks 8, 16 and, following the washout period, at week 20. A summary neuropsychological test score, the NPZ-8, was derived by computing the average of eight neuropsychological test scores standardized for the participant's age and education as previously described [36,37]. The NPZ-8 encompassed the following tests, which are sensitive to HIV-associated cognitive-motor impairment: Timed Gait, Symbol Digit, Grooved Pegboard performed with the dominant and non-dominant hand, Trail Making series A and B, and two computerized reaction time tests (CalCAP system) [37–41]. Normative values were obtained from an HIV-negative neurologically asymptomatic group of individuals enrolled in the Multi-center AIDS Cohort Study [39,40,42].
Proton MRS evaluations
Fifty-one subjects had both baseline and week 16 MRS data and are considered in this analysis. MR evaluations consisted of high-resolution T1-weighted sagittal images and simultaneously acquired high-resolution proton-density and T2-weighted axial images, as previously described . MRS data were obtained with the GE pulse sequence PROBE-P, which is a PRESS sequence with CHESS water suppression [43,44]. MRS parameters included: TE, 35 msec; TR, 3000 msec; voxel size, 6 ml (20 × 20 × 15 μl); 128 acquisitions; spectral width, 2500 Hz; 2000 data points. MRS spectra were acquired from the mid-line posterior parietal cortex (PAR; gray matter), mid-frontal centrum semiovale (CSO; white matter) and basal ganglia (BG; deep gray matter). Five metabolite ratios were measured in each of the three brain regions: NAA/Cr, choline (Cho)/Cr, myoinositol (MI)/Cr, NAA/Cho and NAA/MI. A study of intersite variability in metabolite measurements was performed as recently reported . The results showed that metabolite differences between subjects were likely to reflect inherent biological rather than intersite differences.
One hundred forty subjects were equally distributed across the two study arms (Fig. 1). Sample size calculations were based on a previous study of nimodipine for ADC (ACTG 162) . In an eight-test neuropsychological battery similar to the one used here, the variance of the percent difference from baseline was 34%. Assuming a drop-out rate of 20% as per ACTG 162, this size provided the study with at least 78% power to detect a change of 17% in the neuropsychological test score (NPZ-8) from baseline to week 16 between the two study arms, which is equivalent to a change of 0.5 units in the NPZ-8 score (effect size). One half of a standard deviation in the summary score was previously shown to represent a clinically significant difference (the average difference between neurologically normal and ADC stage 1 individuals, and between ADC stage 1 and ADC stage 2) .
The primary outcome was based on percent difference in the summary neuropsychological test score (NPZ-8) from baseline to week 16 between the memantine and placebo arms assessed by the Kruskal–Wallis test. Additional assessments were also performed at week 8 and after the 4-week washout at week 20. In all cases, the primary efficacy analyses were performed based on available data. Analyses based on carrying forward the last available observation (last observation carried forward – LOCF) were also undertaken. Intermittently missing observations were filled in by interpolating between two observations most closely available in time. All analyses were carried out consistent with the intent-to-treat principle. An analysis of covariance was performed to ensure that changes in neuropsychological performance from baseline to week 16 or week 20 were not associated with changing CD4 cell counts and HIV RNA concentration measured in the cerebrospinal fluid (CSF) or plasma. There were CD4 count or HIV viral load measurements assessed at week 20, so week 16 measurements were carried forward.
Additional analyses, using a longitudinal generalized estimating equations model explored the possibility that memantine treatment may result in improvements among patient subgroups defined by HIV RNA concentration in the CSF or plasma at baseline . ADC improvement was defined as lower ADC stage during the study compared to baseline versus no change or worsening. ADC worsening was defined as higher ADC stage compared to baseline versus no change or improvement. In all cases, statistical models were adjusted for baseline CD4 cell count, CSF and plasma HIV RNA concentration, ZDV use and baseline ADC stage. We also considered interactions between these factors and treatment assignment.
To determine the effects of memantine on brain metabolites at week 16, we carried out a multivariate analysis of covariance model of the week 16 MRS levels on all nine metabolite-by-region combinations (three metabolites measured in three brain regions), adjusting for baseline metabolite levels, race/ethnicity, education, CSF and plasma HIV RNA concentration and CD4 cell count, ZDV use, ADC stage and baseline NPZ-8 score. A forward model selection algorithm was performed to select the most parsimonious statistical model of week-16 MRS levels. Factors were successively entered in the statistical model if they reached statistical significance at least at the 20% level (i.e., if the P value associated with the factor in the model was < 0.20). Associations between categorical data were assessed by the Fisher's exact test. The time from treatment initiation to the occurrence of a serious toxicity was estimated by the Kaplan–Meier approach and compared between the two arms by the log-rank test. All statistical tests were carried out at the 95% level of significance.
The characteristics of the subjects enrolled are summarized in Table 1. One hundred forty subjects with ADC stage 1 (n = 107) and stage 2/3 (n = 33) were randomized to memantine or placebo. There were no differences in age or educational levels between the memantine and placebo treated groups. Most subjects (82%) did not report previous or current injecting drug use. Although the protocol required a 6-week stable antiretroviral regimen prior to enrollment, most subjects enrolled (88.6%) had been on the same regimen for at least 12 weeks. Eighty-eight percent were receiving combined antiretroviral therapies, including a protease inhibitor at baseline. Some recent data suggest that antiretroviral drugs with better central nervous system (CNS) penetration may improve cognitive performance . In this regard, 92% of the subjects were taking at least one drug with good CNS penetration (ZDV, lamivudine, abacavir, indinavir, nevirapine, efavirenz and stavudine). The proportion of subjects on these antiretroviral drugs was not statistically significant between the two treatment groups (P > 0.999). The cohort enrolled had moderate immune suppression, as indicated by a median CD4 lymphocyte count of 274 cells/μl. However, HIV replication was relatively well-controlled; median plasma HIV RNA concentration was 123 copies/ml while the median CSF HIV RNA concentration was below the limits of quantitation (Roche Ultrasensitive Amplicor, limits of quantitation ≥ 50 copies/ml).
Neurological assessment showed that most subjects (76%) had mild neurological disease (ADC stage 1) with a median NPZ-8 score of –1.21. As expected, subjects with advanced ADC (stages 2 and 3) had a median NPZ-8 score of −2.16, which was significantly lower than subjects with mild ADC (P < 0.001). There were no significant differences in any neuropsychological measurement between the two arms at baseline.
Of 140 subjects, 128 remained on study at week 8, 122 at week 16, and 106 at week 20. Reasons for discontinuation are listed in Fig. 1. The majority of patients in both arms completed protocol evaluations. The reasons for treatment discontinuation were similar in both groups. Complete neuropsychological data (including full baseline and follow-up evaluation) were available on 106 subjects at week 8, 93 at week 16, and 94 at week 20 (Table 2). The percent difference of the NPZ-8 data from baseline to week 16 was consistently higher in the memantine arm, and the mean difference between the two arms reached 43% at week 16 (60% versus 17% improvement, respectively) while the median NPZ-8 difference was only 4%, reflecting a higher than expected variability in the NPZ-8 observations in the memantine arm (201% versus the expected 34%; Table 2).
LOCF analysis of neuropsychological performance
Results from the LOCF analyses were consistent with the available-data analyses (Table 2). The mean NPZ-8 difference between the two arms at week 16 was 37%, while the median NPZ-8 difference was 5%. There was no association between maximum dose at week 16 and neuropsychological performance in the memantine and placebo arms.
Analysis of covariance showed no statistically significant associations either between week 16 CD4 cell counts or HIV RNA concentration in plasma or CSF, or their change from baseline to week 16 and the change in NPZ-8 from baseline to week 16 or 20.
Week 20 analysis of neuropsychological performance
In the observed data analysis, at week 20, following the 4-week washout period, the median NPZ-8 difference from baseline between the two arms was 9% (Table 2), yielding a trend favoring the memantine arm (Kruskal–Wallis test, P = 0.054) while in the LOCF analysis (Table 2) the median NPZ-8 difference increased to 10%, reaching significance (P = 0.024).
Response to therapy among mild versus moderate to severe ADC patients
Response to treatment was further assessed by comparing the change in NPZ-8 in subjects with mild ADC and those with moderate to severe impairment (ADC stage 2 or greater) (data not shown). Based on the available data, the results of these analyses were consistent with those shown in Table 2 including the greater variability in NPZ-8 performance among the memantine treated subjects. In contrast, among subjects with ADC stage 2/3, the observed variability in NPZ-8 performance was much reduced.
Response to therapy according to virological indices
In post hoc analyses, the possibility that memantine could benefit a subgroup of ADC subjects was examined by stratifying subjects by their baseline HIV RNA concentration in the CSF and plasma. ADC stage worsened at some point during follow-up in more subjects with detectable virus in the CSF at baseline (8/35, 23%) compared to those with undetectable CSF virus at baseline (6/75, 8%; odds ratio, 3.41; P = 0.021). There was no relationship between worsening ADC and baseline HIV plasma concentration. CD4 cell count was a significant predictor of ADC worsening only among patients with detectable CSF HIV RNA concentration at baseline (P = 0.042).
In those with detectable CSF HIV RNA (n = 35), memantine-treated subjects showed a lesser worsening of ADC stage compared to placebo-treated subjects in the first 12 weeks (P = 0.003, Fig. 2). This trend continued but was not significant at week 16 and 20.
Effects of memantine on brain metabolism and neuronal dysfunction
A proton MRS substudy at baseline and week 16 was performed in 51 subjects (26 in the memantine and 25 in the placebo arm). Significant increases in NAA/Cr were observed among individuals receiving memantine compared to placebo in the frontal white matter and the parietal cortex (P = 0.040, P = 0.023, respectively; Table 3). A trend towards an increase in Cho/Cr in the basal ganglia was also observed in the memantine group compared to placebo (P = 0.065). Analysis of the percent change in NPZ-8 from baseline to week 16 in these 51 subjects showed no difference between the memantine and placebo arms.
We examined baseline factors that may have predicted the effect on NAA/Cr at week 16. Subjects with milder cognitive impairment (ADC stage 1) showed larger NAA/Cr increases in the parietal cortex (P = 0.040), while subjects with lower baseline CSF HIV RNA levels experienced significantly higher NAA/Cr increases in the frontal white matter (P = 0.011). In all cases, the main predictive factor was baseline NAA/Cr level which correlated with higher NAA/Cr levels in both the frontal white matter and parietal cortex. In contrast, race/ethnicity, baseline educational level and CD4 cell counts showed no effect.
Analysis was repeated by treating HIV RNA concentration in the plasma or CSF as a covariate in 33 subjects with available baseline and week 16 HIV RNA data, as reductions in CSF HIV RNA concentration have been shown to improve metabolite levels . The effect of memantine on NAA/Cr remained significant in the white matter and parietal cortex after adjustment for baseline and week 16 CSF and plasma HIV RNA concentration (P = 0.040).
Sixty-one percent of subjects (36/59 subjects) in the memantine arm tolerated the maximum dose of 40 mg/day during week 16; 17% (n = 10) received 30 mg; 19% (n = 11) 20 mg, and the remaining 2% (n = 2) 10 mg. The proportion of subjects reaching the 40 mg dose in the memantine group was significantly lower than in the placebo arm (P = 0.001), in which 46/52 subjects (88.5%) received 40 mg/4 pills; 3 (6%) 30 mg/3 pills; 2 (4%) 20 mg/2 pills; and 1 (2%) 10 mg/1 pill. A total of 116 adverse events were recorded in the placebo arm and 106 in the memantine arm. There were nine subjects in the memantine arm who experienced Grade 1 toxicity during the study and none in the placebo arm. Twenty-four subjects in the memantine arm and 20 in the placebo experienced Grade 2 or higher toxicity, including one memantine and two placebo-treated subjects who experienced Grade 4 toxicity. None of the Grade 4 toxicities were drug-related. There were two deaths during the first 16 weeks, both in the placebo arm. No significant differences between the treatment arms were observed with respect to the frequency of a Grade 2 or greater toxicity, or to the time from treatment initiation until such toxicity developed. The dose of memantine was not associated with the frequency of these events. There were 182 dose modifications (excluding study-prescribed dose escalation and washout), of which 101 occurred in the memantine arm and 81 in the placebo arm. There were no differences in the frequency of or reasons for dose modifications between the two groups with the exception of a small disparity in cases involving disorientation, agitation, insomnia, lightheadedness, photosensitivity and tremors which were observed exclusively among 12 subjects receiving memantine.
Memantine was safe and relatively well tolerated by the cohort of HIV infected individuals with cognitive impairment enrolled in this clinical trial. Its better toxicity profile when compared to other NMDA receptor antagonists such as eliprodil and CNS 1102 likely reflects its ability to effectively block neurotoxic levels of glutamate agonists with relative sparing of neurotransmission .
Based on the primary neuropsychological outcome measure, the NPZ-8, we found no significant difference between the memantine and the placebo arms. The study was powered to detect a 17% difference between the two arms at week 16, which was considered clinically meaningful based on the variability of the neuropsychological measures observed in two previous AACTG trials for ADC [37,45]. While the mean difference in neuropsychological improvement was substantially higher in the memantine arm versus the placebo arm (43%) the median difference was only 4%. This large variability in the NPZ-8 was observed particularly among mildly impaired subjects (ADC stage 1). Such variability may have reflected a number of factors, including differences in demographics or disease-related indices, or the heterogeneity of the disorder among mildly impaired subjects.
Since there were no differences in the demographics or in the virological and immunological indices between the memantine and placebo arms (Table 1), we performed additional analyses that could explain the NPZ-8 variability. These analyses showed that more subjects with detectable CSF HIV RNA at baseline experienced ADC worsening over the course of the study compared to those with undetectable CSF levels at baseline, yielding a 30% annualized risk of cognitive decline in such individuals.
When comparing memantine to placebo-treated subjects with baseline detectable CSF HIV RNA, the rate of cognitive worsening tended to be greater in the placebo arm. Although these results should be interpreted with caution, given the small number of subjects included in this analysis, they raise the possibility that to observe a benefit from a neuroprotective agent, especially in a short trial, subjects with progressive decline need to be enrolled. This is consistent with a recent proposal to reclassify the phenotype of ADC into sub-acute (classical ADC), inactive and active ADC . Alternatively, when combined with the virological data, these findings could argue that optimization of antiretroviral regimens to include CNS penetrating agents (e.g. ZDV, indinavir, abacavir, lamivudine, efavirenz, nevirapine, stavudine) could be considered as a first step in treating HIV subjects with cognitive impairment .
In the washout period there was a trend toward improvement at week 20 which reached significance in the LOCF analysis. The latter result may have reflected either the observations carried forward from weeks 8 or 16, or recovery from memantine-associated toxicity. Fewer memantine-treated subjects were able to tolerate the maximum dose compared to placebo, but there were no significant differences in grade 2 or higher toxicity between the two groups. Alternatively, the possible response may have been due to a delayed effect of treatment, arguing for studies of longer duration (24 weeks) as found in recent trials of Alzheimer's disease [21,22]. Consistent with the latter observation is the drug's known long half-life coupled with the expected prolonged effect of a neuroprotective agent .
We recently showed that decreases in NAA, a marker of neuronal metabolism, including axonal transport in the white matter, may provide a critical step in the pathogenesis of ADC [7,35]. Although the effects were modest, our results complement in vitro studies that have demonstrated that memantine can prevent HIV-associated neuronal injury and suggest that memantine may restore or stabilize neuronal metabolism.
Several conclusions can be drawn from this study. Memantine was safe and relatively well tolerated by patients with HIV-associated cognitive impairment; however, no significant cognitive benefit was observed in the 16 weeks of treatment. Although there was no significant cognitive benefit, proton MRS data suggested that memantine may have a neuroprotective effect. The results of this study emphasize that efficacy clinical trials aimed at neuroprotection for HIV-associated cognitive impairment need to identify subjects at higher risk of cognitive decline (i.e. subjects with detectable CSF HIV RNA despite optimal HAART) and significantly increase the study duration to differentially assess the effect of the putative neuroprotective agent from that of placebo.
The authors thank D. Rausch for generous NIMH support for the ACTG 301 study, A.C. Perkins for administrative assistance, H.J. Moebius, Merz Pharmaceuticals and S. Chen, CNS Medical Affairs, Forest Laboratories. The authors thank Michelle D. Gaugh and Patricia L. Lee for her assistance with manuscript preparation and editing.
Participating Members and Sites
AACTG Operations Office: Stacy A. Bradley. CCG Representatives: Michael Donnelly, James Weihe. Emory University Hospital: Angela Caliendo. San Francisco General Hospital: Richard Price. Stanford University Medical Center: Terrence F. Blaschke. NIAID, DAIDS: Ana I. Martinez, Marjorie Dehlinger. NIH, NIMH, DSIR: Benedetto Vitiello. Neurobiological Technology Inc: Lisa Carr.
Beth Israel Medical Center (NY): Daniel MacGowan, Donna Mildvan. Harbor-UCLA: Gildon Beall, Mario Guerrero, Jorge Jovicich, Oliver Speck, Mallory Witt. Harvard/Massachusetts General Hospital ACTU: Igor Koralinik, Carol Delaney, Beth Israel Deaconess Medical Center; Sandford Auerback, Boston Medical Center; Nagagopal Venna, Gilbert Roy, Jr. Teri Flynn, Massachusetts General Hospital. Harvard School of Public Health: Marc Vallée, Natasa Rajicic. Mount Sinai Medical Center: Garnett Simpson, Pieter Gerits. Northwestern University Medical Center: Bruce Cohen, Catherine Cooper. Rush Medical College, Cook County Hospital: David Barker, Russell Bartt. State University of New York at Buffalo: Ross G. Hewiit, Holly Ingelfinger-Lopez. University of California at Los Angeles: Suzette A. Chafey. University of California at San Diego: Ron Snyder, Jill Kunkel, Julie Rippeth. University of Hawaii: Debbie Ogata-Arakaki, Nancy Hanks, Scott Souza, Queen's Medical Center. University of Kentucky: Richard Greenberg. University of Miami: Karl Goodkin, Margaret Fischl. University of Nebraska Medical Center: Susan Swindells, Howard E. Gendelman. University of Pennsylvania Medical Center: Robert Lenkinski. University of Rochester:Richard Reichman, Jianhui Zhong, Mary Shoemaker. University of Texas Medical Center, Galveston: Robert R. McKendall, Leena Ketonen, Richard B. Pollard, Michael Borucki, Karen Waterman, Gloria Carrera. University of Washington: Margot Schwartz, N. Jeanne Conley, Ann C. Collier, Washington University: David B. Clifford, Lisa Kessels, Mary Gould.
Sponsorship: The MRS consortium is supported by R01NS36524. Support was also provided from R01NS34626, R01RR13213, R01NS38834, AI-38855, The University of Rochester CRC 5MO1 RR00044 and the NIAID from AI38858 and AI03855.
Normative data were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at The Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick, Alvaro Muñoz), Howard Brown Health Center and Northwestern University Medical School (John Phair), University of California, Los Angeles (Roger Detels, Beth Jamieson), and University of Pittsburgh (Charles Rinaldo, PhD). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043,UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041.
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