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Original Contribution |

Attenuated Central Nervous System Infection in Advanced HIV/AIDS With Combination Antiretroviral Therapy FREE

Justin C. McArthur, MBBS, MPH; Michael P. McDermott, PhD; Daniel McClernon, BS; Coryse St Hillaire, BS; Kathy Conant, MD; Karen Marder, MD, MPH; Giovanni Schifitto, MD; Ola A. Selnes, PhD; Ned Sacktor, MD; Yaakov Stern, PhD; Steve M. Albert, PhD; Karl Kieburtz, MD, MPH; Joy A. deMarcaida, MD; Bruce Cohen, MD; Leon G. Epstein, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Md (Drs McArthur, Conant, Selnes, and Sacktor and Ms St Hillaire); Departments of Neurology (Drs McDermott, Schifitto, Kieburtz, and deMarcaida) and Biostatistics (Dr McDermott), University of Rochester, Rochester, NY; GlaxoSmithKline, Research Triangle Park, NC (MrMcClernon); Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain (Drs Marder, Stern, and Albert) and Mailman School of Public Health, (Dr Albert), Columbia University, New York, NY; Department of Neurology, Northwestern University, Chicago, Ill (Dr Cohen); and Division of Pediatric Neurology, Children’s Memorial Hospital, Chicago (Dr Epstein).


Arch Neurol. 2004;61(11):1687-1696. doi:10.1001/archneur.61.11.1687.
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Published online

Background  Before the introduction of combination antiretroviral therapy (CART), neurological disease correlated with cerebrospinal fluid (CSF) levels of human immunodeficiency virus (HIV) RNA.

Objective  To investigate the relationships among HIV RNA levels, immune activation markers, and neurological status in patients receiving CART.

Design  Multicenter cohort study.

Setting  Academic neurology departments.

Patients  A total of 371 patients unselected for neurological complaints and with CD4 cell counts less than 200/μL or with cognitive symptoms and CD4 cell counts less than 300/μL were enrolled into the Northeastern AIDS Dementia cohort in 1998-2002. Diagnoses of HIV-associated dementia (HIV-D) and minor cognitive-motor disorder (MCMD) were obtained with a computerized algorithm. Plasma and CSF levels of HIV RNA, monocyte chemotactic protein 1, macrophage colony-stimulating factor, and tumor necrosis factor α were quantified.

Results  The mean ± SD age was 41.5 ± 7.2 years, and the mean ± SD educational level was 12.3 ± 2.2 years. Seventy percent of the cohort was black, and 30% were women. The mean ± SD CD4 cell count was 136.8 ± 87.9/μL, and CART was used in 71%. Twenty-nine percent of the patients were unimpaired (n = 106), 36% had MCMD (n = 133), and 35% had HIV-D (n = 128). Mean log10 CSF HIV RNA copies per milliliter was 2.6 ± 0.8, with no differences among the neurological groups, even after adjustments for baseline CD4 cell counts and antiretroviral therapy. Cerebrospinal fluid HIV RNA was undetectable in 47% of unimpaired, 46% of MCMD, and 43% of HIV-D patients (P = .91). Plasma levels of monocyte chemotactic protein type 1 and tumor necrosis factor α correlated weakly with HIV RNA levels but did not distinguish those with neurological deficits.

Conclusions  In contrast to observations in individuals not treated with CART, we found no relationshipbetween CSF markers and neurological status in this CART-using cohort with advanced HIV/AIDS. This was not explicable by demographic differences or plasma virological control. CART may substantially attenuate the degree of central nervous system HIV infection and immune activation, and in CART users, CSF HIV RNA and immune activation markers may fail to discriminate milder degrees of HIV-D and MCMD.

Figures in this Article

Once established in the central nervous system (CNS),1,2 human immunodeficiency virus (HIV) produces a chronic infection that predominantly involves perivascular macrophages, with restricted infection of astrocytes.3 The quantification of HIV RNA in plasma is a powerful predictor of disease progression.4,5 The combined measurement of plasma HIV RNA and CD4 lymphocytes provides an even more accurate prognostication6 and can predict the development of HIV-associated dementia (HIV-D).7

Several research groups810 have demonstrated a significant relationship between cerebrospinal fluid (CSF) HIV RNA levels and the severity of HIV-D, primarily before the introduction of combination antiretroviral therapy (CART) in 1996. In the pre-CART era, Cinque et al11 showed a significant relationship between CSF HIV RNA levels and HIV-associated neuropathologic changes. McClernon et al12 also determined that brain HIV RNA levels were generally significantly elevated with severe, but not mild, HIV-D. Persistent elevations in CSF simian immunodeficiency virus RNA levels also correlated with the development of simian immunodeficiency virus encephalitis.13 Thus, increasing levels of lentivirus replication in the CNS contribute to the development of neurological disease.14

The introduction of CART has resulted in virological suppression and improved survival.15 Also, CART has been associated with improvements in cognitive performance16 and a decreased incidence of HIV-D,15,17 as well as changes in imaging markers.18,19 Reductions in CSF HIV RNA levels with CART correlate with improved neuropsychological performance.2022 Specific CART regimens may be more effective for CNS virological control. Thus, more prominent viral load reductions were observed in individuals receiving CNS-penetrating CART regimens than regimens considered to be less penetrant.23 A recent trial24 of established HIV-D confirmed additional virological suppression in plasma and CSF with adjunctive abacavir added to CART. Baseline levels of CSF HIV RNA were significantly lower than those observed in pre-CART studies. These observations suggest that the phenotype and the biological markers of HIV-D have undergone an evolution and may have been attenuated by CART. Paradoxically, our group17 recently demonstrated that the prevalence of HIV-associated cognitive impairment remains high among individuals with advanced infection. Herein we examine the effect of CART in a large neurological cohort on HIV RNA and immune activation markers, and their relation to cognitive impairment.

SAMPLE

Beginning in 1998, the Northeastern AIDS Dementia cohort recruited individuals with advanced HIV infection to determine the predictors of HIV-D. Patients were recruited from infectious disease clinics or through targeted advertising initially at 3 sites—Columbia University, Johns Hopkins University, and the University of Rochester—and, beginning in 1999, at Northwestern University (data from Northwestern University are not included owing to the small numbers). All patients were reimbursed for their participation and provided informed consent, and the study was approved by the respective institutional review boards. Patients were eligible for inclusion in the cohort if they were HIV seropositive and had CD4 cell counts less than 200/μL or CD4 cell counts less than 300/μL with cognitive impairment on neuropsychological testing (defined as performance 2 SD below the appropriate mean on 1 test or 1 SD below the mean on 2 tests). Patients with CD4 cell counts less than 200/μL were not selected for any neurological complaints. Patients were excluded if they were nonambulatory or if they had other neuropsychiatric conditions (eg, current or past CNS infection, head injury, or major psychiatric disease) that might cause cognitive impairment. Patients were not excluded if they had a history of injection drug use or alcohol abuse.

PROCEDURES

Clinical assessments were performed semiannually. At each visit, patients underwent a standardized neurological examination; completed a battery of neuropsychological, functional, and psychiatric assessments; and had blood samples taken for laboratory studies. Samples of CSF were collected every 12 months. In this article, we focus on data collected from the baseline evaluation. Plasma and CSF HIV RNA levels were determined by one of us (D.M.) using the NucliSens assay (Organon-Teknika, Durham, NC) at GlaxoSmithKline. The limit of detection on this assay was 80 copies/mL. Selected immune activation markers were assayed by 1 of us (K.C.) using commercial enzyme-linked immunosorbent assay kits at Johns Hopkins University: tumor necrosis factor α (TNF-α), monocyte chemotactic protein type 1 (MCP-1), and macrophage colony-stimulating factor (M-CSF) (Quantikine; R&D Systems, Minneapolis, Minn) (limit of detection, 31.2 pg/mL).

DEMOGRAPHIC AND ANTIRETROVIRAL THERAPY DATA

Independent variables included age at initial visit, years of HIV infection, years of education, sex, race, medical center of enrollment, patterns of antiretroviral therapy at baseline (categorized as none currently, monotherapy, dual therapy, or CART, defined as ≥3 Food and Drug Administration–approved antiretroviral agents). The patterns of antiretroviral use were determined only by self-report, with no check of pharmacy records or medication adherence.

NEUROLOGICAL AND MEDICAL EXAMINATIONS

A standardized history of AIDS diagnoses was collected, and the presence of any single illness was used as an independent variable. The neurological examination was designed to capture signs associated with HIV-D and included the macroneurological examination created by the AIDS Clinical Trials Group and the motor subscale (part III) of the Unified Parkinson’s Disease Rating Scale25 to rate extrapyramidal signs.

NEUROPSYCHOLOGICAL TESTING

The neuropsychological battery was designed to delineate HIV-D and HIV-associated minor cognitive-motor disorder (MCMD). The 8 tests covered 6 domains. Verbal memory was assessed using the Rey Auditory Verbal Learning Test.26 Visual memory was assessed using the Rey-Osterrieth Complex Figure Delayed Recall Test.26 Constructional skills were assessed using the Rey-Osterrieth Complex Immediate Recall Test. Psychomotor skills were measured using the Digit Symbol Test,27 and motor skills were assessed using the Grooved Pegboard (both hands)28 and Timed Gait tests. Reaction time was measured using the California Computerized Assessment package.29 Frontal systems were assessed using the Verbal Fluency30 and Odd-Man-Out31 tests. General intellectual performance was assessed using the New Adult Reading Test.32,33 Performance was judged relative to normative data as previously described.34,35

FUNCTIONAL MEASURES AND PSYCHIATRIC ASSESSMENT

Selected functional measures measured how cognitive deficits compromised everyday function and were derived from the Instrumental Activities of Daily Living scales,36 the Katz Instrumental Activities of Daily Living/Lawton Personal Self-Maintenance Scale,37 and the role functioning items of the Medical Outcomes Study.38 Two functional outcomes that reflect stress and stamina were also included: the Karnofsky performance scale39 and the Medical Outcomes Study physical function subscale.38

The presence of depression was determined using the Beck Depression Inventory, a widely used self-rating instrument for depressive symptoms.40,41 Patients with a level of 16 or greater were classified as clinically depressed.

CLINICAL CATEGORIZATION

We categorized patients according to neurological status in 2 separate ways. First, the extensive neurological, neuropsychological, functional, and psychiatric assessments were used to classify patients as not impaired, HIV-associated MCMD, or HIV-D according to the American Academy of Neurology (AAN) criteria.34,42 Second, we used a modified version of the Memorial Sloan-Kettering scale to rate dementia severity.43,44 We assessed the reliability of this scale in consensus conferences, with κ statistics ranging from 0.7 to 0.91.45

STATISTICAL ANALYSIS

The independent variables of interest were levels of HIV RNA, MCP-1, TNF-α, and M-CSF in plasma and CSF. These were treated as continuous log-transformed (base 10) variables. Logistic regression was used to examine the associations between the independent variables and outcome. For the AAN classification, separate models were fitted for the outcome of no impairment vs MCMD/HIV-D and the outcome of no impairment/MCMD vs HIV-D. Similar analyses were performed for the outcome of modified Memorial Sloan-Kettering stage (<1 vs ≥1). All analyses included adjustment for study site and CD4 count (log transformed). Separate analyses were performed that adjusted for CART use and that compared results in CART-naive patients with those in CART recipients. In a separate analysis, plasma HIV RNA levels were used as a surrogate for virological suppression, independent of reported antiretroviral use.

Pairwise comparisons of demographic and clinical variables among AAN classifications were performed using t tests and χ2 tests, as appropriate. Spearman rank correlations were used to describe associations. Values are given as mean ± SD.

PATIENT CHARACTERISTICS

The demographic, clinical, virological, and immune characteristics of the cohort are detailed in Table 1, Table 2, and Figure 1. Three hundred seventy-one patients were enrolled: 196 at Johns Hopkins University, 104 at Columbia University, and 71 at the University of Rochester. Seventy percent of the cohort was male, and 70% were black. The mean patient age was 41.5 ± 7.2 years, and the mean educational level was 12.3 ± 2.2 years. The mean IQ measured using the New Adult Reading Test was 96.9 ± 10.8. The cohort had had documented HIV infection for a mean of 7.5 ± 4.2 years, and the mean CD4count was 136.8 ± 87.9/mm3; 61% of patients reported an AIDS-defining illness, and 36% had symptomatic sensory neuropathy.

Table Graphic Jump LocationTable 1.  Baseline Demographic and Clinical Characteristics Across AAN Dementia Classification Categories
Table Graphic Jump LocationTable 2.  Baseline Laboratory Results Across AAN Dementia Classification Categories and Treatment Exposure
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Figure 1.

Distribution of plasma human immunodeficiency virus RNA levels based on combination antiretroviral therapy (CART) exposure at the baseline visit. The proportion of patients with high levels of plasma viremia (10 000-100 000 and >100 000 copies/mL) was statistically significantly higher among nonusers of CART. Users of only 1 or 2 antiretrovirals (n = 15) are not displayed.

Graphic Jump Location
CATEGORIZATION OF PATIENTS USING THE AAN ALGORITHM

One hundred six patients were not impaired, 133 had MCMD, and 128 had HIV-D. There were site-specific differences in the proportions of patients with HIV-D: 14% at Rochester, 44% at Columbia, and 37% at Johns Hopkins. Using the modified Memorial Sloan-Kettering criteria for categorization, 4% of patients were rated as 0, 46% as 0.5, 24% as 1 (mild HIV-D), 17% as 2 (moderate HIV-D), and 9% as 3 (severe HIV-D). More patients classified as either MCMD or HIV-D had neurological abnormalities and symptomatic sensory neuropathy, were clinically depressed, and reported self-maintenance and instrumental ADL deficits than unimpaired patients (Table 1). Patients with MCMD and HIV-D also had lower scores on the Karnofsky and physical function scales than unimpaired patients (Table 1).

PATTERNS OF ANTIRETROVIRAL THERAPY AND VIROLOGICAL CONTROL

Twenty-four percent of patients were not using any antiretroviral medications at the baseline visit, 5% were using 2 antiretrovirals, and 71% reported the use of CART. Only 19 patients (5%) were antiretroviral naive at baseline. The proportion of individuals with undetectable plasma HIV RNA levels (<80 copies/mL), independent of antiretroviral use, was 22% overall, and 22% had plasma HIV RNA levels greater than 100 000 copies/mL. The patterns of antiretroviral use did not differ significantly across the neurological groups (Tables 1 and 2). Mean log10 plasma HIV RNA copies per microliter were, in general, lower among CART users than nonusers, but did not differentiate the neurological groups (Table 2).

ASSOCIATIONS BETWEEN VIRAL LOAD AND IMMUNE MARKERS AND NEUROLOGICAL STATUS

Forty-six percent of patients had undetectable CSF HIV RNA levels (<80 copies/mL), with no significant differences among the neurological groups. Overall, the mean log10 CSF HIV RNA level was 2.6 ± 0.8 copies/mL, with group differences (Figure 2 and Table 2). For patients not using antiretrovirals, mean log10 CSF HIV RNA levels were higher and tended to increase according to dementia status (unimpaired, 2.8 ± 0.7 copies/mL; MCMD, 2.9 ± 1.1 copies/mL; and HIV-D, 3.5 ± 0.8 copies/mL). By contrast, for patients taking CART, mean levels were lower and unrelated to dementia status (unimpaired, 2.4 ± 0.8 copies/mL; MCMD, 2.5 ± 0.8 copies/mL; and HIV-D, 2.4 ± 0.7 copies/mL) (Table 2 and Figure 3). No differences were noted for mild, moderate, or severe HIV-D. Similar patterns were seen for mean log10 plasma HIV RNA levels stratified by treatment. For patients not taking antiretrovirals, mean log10 plasma HIV RNA levels tended to increase according to dementia status (unimpaired, 4.1 ± 1.3 copies/mL; MCMD, 4.9 ± 0.9 copies/mL; and HIV-D, 4.8 ± 1.0 copies/mL). For patients taking CART, mean log10 plasma HIV RNA levels were relatively low and unrelated to dementia status (unimpaired,3.5 ± 1.4 copies/mL; MCMD, 3.7 ± 1.2 copies/mL; and HIV-D, 3.4 ± 1.2 copies/mL) (Figure 4). Mean log10 values of immune activation markers did not differ with respect to dementia status except that CSF TNF-α levels were lower in patients with HIV-D than in unimpaired patients (Table 2).

Place holder to copy figure label and caption
Figure 2.

Cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA levels stratified by American Academy of Neurology (AAN) classification (unimpaired, minor cognitive-motor disorder [MCMD], and HIV-associated dementia [HIV-D]). There were no statistically significant differences in CSF HIV RNA levels using the computerized algorithm to categorize patients. The thick horizontal lines represent mean values; boxes, 25th and 75th percentiles; and error bars, outlier values.

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Place holder to copy figure label and caption
Figure 3.

Cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA levels stratified by Memorial Sloan-Kettering (MSK) stage. There were no statistically significant differences in CSF HIV RNA levels using clinical consensus to categorize patients. The thick horizontal lines represent mean values; boxes, 25th and 75th percentiles; and error bars, outlier values.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Distribution of the cohort by neurological status (unimpaired, minor cognitive-motor disorder [MCMD], and human immunodeficiency virus–associated dementia [HIV-D]), stratified by the use of combination antiretroviral therapy (CART) and the presence of high levels of plasma viremia (defined as ≥10 000 copies/mL) at baseline. A greater proportion of nonusers with HIV-D have high-level plasma viremia while a greater porportion of unimpaired CART users have high levels of plasma viremia. Among CART users, there are no significant differences by neurological status.

Graphic Jump Location

The logistic regression analyses did not demonstrate any significant associations between the measures of viral load and immune activation and neurological grouping using either the AAN criteria (Table 3 and Table 4) or the modified Memorial Sloan-Kettering scale (Table 5). The results did not differ substantially after adjustment for antiretroviral regimen or plasma HIV RNA levels (a surrogate of virological suppression independent of reported CART use). The results for AAN dementia classification (Table 3 and Table 4) suggested a weak association between HIV RNA levels and dementia status in those not taking antiretrovirals, although the interactions between HIV RNA levels and CART were not statistically significant.

Table Graphic Jump LocationTable 3.  Associations Between HIV RNA and Immune Markers and HIV-Associated Dementia
Table Graphic Jump LocationTable 4.  Associations Between HIV RNA and Immune Markers and MCMD/HIV-Associated Dementia Combined
Table Graphic Jump LocationTable 5.  Associations Between HIV RNA and Immune Markers and MSK Stage 1 or Higher
RELATIONSHIPS AMONG THE VIROLOGICAL AND IMMUNE ACTIVATION MARKERS

Correlation coefficients were calculated for all pairs of virological and immune activation markers. Most of these correlations were relatively weak (r<0.30), except for plasma vs CSF HIV RNA level (r = 0.37), plasma HIV RNA level vs plasma MCP-1 level (r = 0.32), plasma HIV RNA level vs CSF MCP-1 level (r = 0.31), plasma vs CSF MCP-1 level (r = 0.49), and plasma MCP-1 level vs plasma TNF-α level (r = 0.44) (P<.001 for all). 

Neither plasma nor CSF HIV RNA levels were statistically significantly associated with HIV-D or HIV-associated MCMD. In addition, the immune activation markers MCP-1, M-CSF, and TNF-α were not associated with neurological status in either plasma or CSF. Exposure to CART by itself did not account for the lack of association between neurological status and CSF viral load measures.

Previously, a strong correlation was noted between CSF HIV RNA levels and the severity of HIV-D. However, these studies either focused on severely demented individuals23 or predated the introduction of CART.810 In contrast, we show relatively low CSF HIV RNA levels in patients treated with CART, and, furthermore, we found no definitive relationship among neurological status, CSF HIV RNA levels, and markers of immune activation. This suggests that the natural history of HIV-D has been altered by the widespread use of CART.

In our 1997 study,10 there was a graded relationship between the severity of neurological disease and CSF HIV RNA levels. We observed a similar relationship for plasma and CSF HIV RNA levels in the present study for patients not using CART but not for CART users. A recent placebo-controlled trial46 of a TNF-α antagonist in HIV-D found that 79% of patients with HIV-D were using CART and had a mean log10 CSF HIV RNA level of 2.3 (2117 copies/mL). This is comparable to the mean log10 CSF level of 2.58 in our cohort. The frequency of undetectable CSF HIV RNA levels was approximately 70% in the TNF-α antagonist trial and was 58% in the trial of abacavir add-on therapy for HIV-D.24 These rates are comparable to the 46% observed in our cohort and suggest that CSF HIV RNA levels are suppressed by CART. Ultrasensitive assays were not used in these studies, so it is plausible that very low levels of CSF HIV RNA might not have been detected.

Our results suggest that the measurement of levels of CSF HIV RNA and selected immune activation markers does not distinguish neurological status in patients with advanced HIV receiving CART. There are several possible explanations for the relatively low levels of CSF HIV RNA and immune activation markers in our cohort. There are inherent limitations of a selected cohort such as this. First, we considered the possibility of a selection bias with recruitment of “long-term” survivors, who perhaps have different patterns of HIV replication. This seems unlikely given that 1 of the entry criteria was a CD4 count less than 200/μL; thus, most patients had profound immunosuppression. Again, most of the cohort was unselected for any neurological symptoms, and the racial characteristics were representative of the state of the HIV epidemic in New York and Maryland.47

Second, the cohort had a high rate of neurocognitive impairment, comparable to that in the pre-CART era. The prevalence of neurological impairment in the Dana cohort17 (with identical entry criteria) in the pre-CART era in 1994 was 23.2%, comparable to the current rate of 19.8%. In the statistical analyses, we examined the effect of CART by adjusting for the reported use of CART. There were no differences in our findings, but this may reflect the relatively high use of CART overall. We also adjusted for plasma HIV RNA as a surrogate for virological control and again could not demonstrate associations between marker levels and clinical grouping. Third, another factor that must be considered is the potential for nonspecific neurocognitive impairments unrelated to CNS HIV infection to “dilute” the results. Our cohort has a relatively high rate of drug and alcohol use and of depression, but there were no associations among these factors and the virological measures or immune activation markers. This cohort showed a high rate of self-reported depression, but this has been reported from multiple studies among individuals with advanced HIV/AIDS.48 In HIV/AIDS and other neurological diseases, including Parkinson disease, most studies have not determined any specific impact of depressive symptoms on neurocognitive functioning.49,50 We, therefore, believe that these potential confounds did not contribute to our findings. Misclassification of neurological status was minimized by using a validated computerized algorithm, and we observed similar results using a clinical categorization. Furthermore, we have shown a high degree of agreement for these classifications.45

Another explanation for the lack of any observable relationship between neurological state and CSF HIV RNA levels is that brain levels of HIV RNA may in fact be low in this group, reflecting a lesser degree of productive CNS HIV replication. The concept that CART is inducing an attenuated form of HIV encephalitis manifest by less severe HIV-associated cognitive impairment has been recently proposed by Brew51 and Kusdra et al52 and is supported by a reduced frequency of severe HIV encephalitis in an autopsy series in the CART era.53 Two pathological studies in the CART era have observed either no temporal changes in the frequency of mild HIV-associated neuropathologic changes54 or an actual increased frequency of mild encephalitis.55 It remains plausible that the neurological disorders that we observed had developed before exposure to CART and that the baseline examination of CART users reflected these earlier CNS insults.

Most Northeastern AIDS Dementia cohort patients (71%) were receiving CART at baseline. This mirrors the national patterns of CART use and use in HIV-seropositive cohorts.56 Several studies57,58 have shown that either dual therapy or CART can suppress CSF HIV RNA levels rapidly, particularly in antiretroviral-naive individuals. Cerebrospinal fluid virological suppression is correlated with predicted CNS antiretroviral drug penetrance23; however, neurocognitive improvement with CART seems to be independent of this variable.59 The principal effect of CART may occur outside the CNS, perhaps by reducing the proportion of circulating activated monocytes, which are the cells presumed to carry HIV into the brain.60

We chose to examine selected soluble immune markers in this study, focusing particularly on those that reflected activation of astrocytes and CNS macrophages. There was a degree of interdependence for many of these measures, as has been previously reported.61 The β chemokine MCP-1 has been shown to be significantly elevated in CSF in HIV-D.62,63 Produced by astrocytes and macrophages, this chemokine may play a role in attracting monocytes into the CNS.62 Levels of CSF MCP-1 are elevated in association with HIV-D and its pathological correlate, HIV encephalitis. In milder degrees of impairment, MCP-1 levels are elevated, although to a lesser degree.64 Levels of CSF MCP-1 correlated with high CSF-plasma HIV RNA ratios and did not decline with CART.23 In simian immunodeficiency virus infection, an elevated ratio of CSF-plasma MCP-1 predicts the subsequent development of encephalitis.65 We noted no elevations in either plasma or CSF levels of MCP-1 or in the CSF-plasma MCP-1 ratio.

Tumor necrosis factor α is produced by activated microglia and macrophages, and levels are elevated in HIV/AIDS.66 Tumor necrosis factor α has been associated with neurotoxicity in vitro, and it may also stimulate the release of matrix metalloproteinases (MMPs) and other inflammatory mediators from cells, including astrocytes. Like MCP-1, TNF-α messenger RNA levels are elevated in association with HIV-D.67 In contrast to earlier studies that showed elevated serum levels,68 we actually noted lower levels of CSF TNF-α in patients with HIV-D.

Macrophage colony-stimulating factor is produced by cell types, including astrocytes, and induces CD16 expression on monocytes and their activation.69,70 Elevated M-CSF levels in CSF71 and serum2 have been observed in HIV-D; however, levels were not elevated in the present study. In a recent HIV-D trial72 in which most participants were using CART, CSF levels of interleukin 6, MIP-1β, and MCP-1 were comparable to levels in neurologically healthy HIV-seropositive patients.46,72 Combined with our observations, these results suggest that levels of immune activation markers are less frequently elevated in contemporary CART cohorts, at least compared with studies from 5 to 10 years ago.

Our observations may have a parallel with syphilis, in which reductions in the frequency of late-stage neurological manifestations have been attributed to the widespread incidental use of antibiotics. Further evidence that antiretroviral therapy may have led to changes in the patterns of progression of HIV-D comes from clinical studies. Before CART, only a third of HIV-D cases survived longer than 12 months.73 In contrast, almost two thirds of patients with HIV-D improved neurologically after CART.74

In summary, in this cohort with advanced HIV/AIDS, we found no significant associations between plasma or CSF HIV RNA levels, immune activation markers, and neurological status for patients using CART. This finding was not explicable by demographics or levels of plasma virological control. We suggest that CSF HIV RNA and immune activation markers are suppressed and that the severity of neurological disease may be attenuated by CART. Although the incidence of HIV-D has dropped by at least 50% since the introduction of CART,17,75 the prevalence of HIV-D has actually risen from 6.6 per 100 person-years in 1994 to 10.1 in 2000,76 reflecting improving survival. This rising prevalence reinforces the necessity to develop sensitive and valid predictive markers for HIV-D. Recently, CSF HIV RNA levels were found to predict development of neuropsychological impairment,77 and longitudinal study of the Northeastern AIDS Dementia cohort will allow us to relate clinical changes to temporal changes in viral load and immune activation markers.

Correspondence: Justin C. McArthur, MBBS, MPH, Department of Neurology, The Johns Hopkins University School of Medicine, 600 N Wolfe St, Baltimore, MD 21287-7609 (jm@jhmi.edu).

Accepted for Publication: January 30, 2004.

Author Contributions:Study concept and design: McArthur, McDermott, Marder, Schifitto, Sacktor, Stern, Albert, Kieburtz, deMarcaida, and Epstein. Acquisition of data: McArthur, McClernon, St Hillaire, Conant, Marder, Schifitto, Selnes, Stern, Albert, deMarcaida, Cohen, and Epstein. Analysis and interpretation of data: McArthur, McDermott, St Hillaire, Schifitto, Albert, Kieburtz, deMarcaida, and Epstein. Drafting of the manuscript: McArthur and Schifitto. Critical revision of the manuscript for important intellectual content: McArthur,McClernon, St Hillaire, Conant, Marder, Schifitto, Selnes, Sacktor, Stern, Albert, Kieburtz, deMarcaida, Cohen, and Epstein. Statistical analysis: McDermott, McClernon, and Albert. Obtained funding: McArthur, Marder, Schifitto, Kieburtz, and Epstein. Administrative, technical, and material support: McArthur, St Hillaire, Conant, and Schifitto. Study supervision: McArthur, Selnes, Sacktor, Stern, Albert, and Kieburtz.

Funding/Support: This study was supported by grants NS36519, NS44807, NS49465, RR00522, RR00044, and RR00645 from the National Institutes of Health, Bethesda, Md.

Acknowledgment: Additional research personnel who participated in the study were George Todak, MSW, Ronda Friedman B. Clouse, RN, and Carmen Polanco (Columbia University); Deneen Esposito, BA, Molly Wilcox, BS, Jason Creighton, BS, and Amanda Barnes, BS (The Johns Hopkins University); and Kim Cruttenden, BS, Connie Orme, BA, Donna Palumbo, PhD, Larry Preston, and Keith Bourgeois, BS (University of Rochester).

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McClernon  DRLanier  RGartner  S  et al.  HIV in the brain: RNA levels and patterns of zidovudine resistance. Neurology 2001;571396- 1401
PubMed Link to Article
Zink  MCSuryanarayana  KMankowski  JL  et al.  High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 1999;7310480- 10488
PubMed
Sei  SSaito  KStewart  SK  et al.  Increased human immunodeficiency virus (HIV) type 1 DNA content and quinolinic acid concentration in brain tissues from patients with HIV encephalopathy. J Infect Dis 1995;172638- 647
PubMed Link to Article
Brodt  HRKamps  BSGute  PKnupp  BStaszewski  SHelm  EB Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997;111731- 1738
PubMed Link to Article
Sacktor  NCSkolasky  RLLyles  RHEsposito  DSelnes  OAMcArthur  JC Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors. J Neurovirol 2000;684- 88
PubMed Link to Article
Sacktor  NMcDermott  MPMarder  K  et al.  HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 2002;8136- 142
PubMed Link to Article
Chang  LErnst  TLeonido-Yee  M  et al.  Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 1999;53782- 789
PubMed Link to Article
Sacktor  NCPomper  MGHorska  ABarker  PBMcArthur  JC Magnetic resonance spectroscopic imaging measures metabolite changes during therapy for HIV-associated cognitive impairment [abstract]. Neurology 2000;54A252
Link to Article
Marra  CMCoombs  RWCollier  AC Changes in CSF and plasma HIV-1 RNA and in neuropsychological test performance after starting HAART.  Paper presented at: Sixth Conference on Retroviruses and Opportunistic infections; February 2, 1999; Chicago, Ill
Deutsch  REllis  RJMcCutchan  JAMarcotte  TDLetendre  SGrant  I AIDS-associated mild neurocognitive impairment is delayed in the era of highly active antiretroviral therapy. AIDS 2001;151898- 1899
PubMed Link to Article
Ellis  RJGamst  ACCapparelli  E  et al.  Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 2000;54927- 936
PubMed Link to Article
De Luca  ACiancio  BCLarussa  D  et al.  Correlates of independent HIV-1 replication in the CNS and of its control by antiretrovirals. Neurology 2002;59342- 347
PubMed Link to Article
Brew  BJHalman  MCatalan  J  et al Abacavir in AIDS dementia complex: efficacy and lessons for future trials. Neurology In press
Fahn  SMarsden  CCaine  D Recent Developments in Parkinson's Disease.  Florham Park, NJ: Macmillan Healthcare Information; 1987
Rey  A L’examen psychologique dans les cas d'encephalopathie traumatique. Arch Psychol (Frankf) 1941;28286- 340
Wechsler  D Wechsler Adult Intelligence Scale Revised.  New York, NY: Psychological Corporation; 1981
Klove  H Clinical neuropsychology. Med Clin North Am 1963;471647- 1658
PubMed
Miller  ENSatz  PVisscher  B Computerized and conventional neuropsychological assessment. Neurology 1991;411608- 1616
PubMed Link to Article
Benton  ALHamsher  KD Multilingual Aphasia Examination.  Iowa City: University of Iowa; 1976
Flowers  KARobertson  C The effect of Parkinson's disease on the ability to maintain a mental set. J Neurol Neurosurg Psychiatry 1985;48517- 529
PubMed Link to Article
Nelson  HEO’Connell  A Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex 1978;14234- 244
PubMed Link to Article
Stern  YAndrews  HPittman  H  et al.  Diagnosis of dementia in a heterogeneous population: development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol 1992;49453- 460
PubMed Link to Article
Dana Consortium on Therapy for HIV Dementia and Related Cognitive Disorders, Clinical confirmation of the American Academy of Neurology algorithm for HIV-1 associated cognitive/motor disorder. Neurology 1996;471247- 1253
PubMed Link to Article
Concha  MSelnes  OAMcArthur  JC  et al.  Normative data for a brief neuropsychological test battery in a cohort of injecting drug users. Int J Addict 1995;30823- 841
PubMed
Lawton  MPBrody  EM Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9179- 186
PubMed Link to Article
Katz  SFord  AMoskowitz  RWJackson  BAJaffe  MW Studies of illness in the aged: the index of ADL. JAMA 1963;185914- 919
PubMed Link to Article
Stewart  ALWare  JE Measuring Function and Well-Being: The Medical Outcomes Study Approach.  Durham, NC: Duke University Press; 1993
Karnofsky  DAAbelman  WHCarver  LF  et al.  The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1948;1634- 656
Link to Article
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed Link to Article
Beck  ATBeamesderfer  A Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry 1974;7151- 169
PubMed
Working Group of the American Academy of Neurology AIDS Task Force, Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type-1 (HIV-1) infection: report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 1991;41778- 785
PubMed Link to Article
Price  RWBrew  BJ The AIDS dementia complex. J Infect Dis 1988;1581079- 1083
PubMed Link to Article
Price  RWSidtis  JJ Evaluation of the AIDS dementia complex in clinical trials. J Acquir Immune Defic Syndr 1990;3(suppl 2)S51- S60
PubMed
Marder  KAlbert  SMMcDermott  MP  et al.  Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment. Neurology 2003;601467- 1473
PubMed Link to Article
Clifford  DBMcArthur  JCSchifitto  G  et al.  A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor impairment. Neurology 2002;591568- 1573
PubMed Link to Article
Centers for Disease Control and Prevention, Cases of HIV infection and AIDS in the United States, 2002. HIV AIDS Surveill Rep 2003;14A1- A7
Lyketsos  CGHoover  DRGuccione  M  et al.  Changes in depressive symptoms as AIDS develops: the Multicenter AIDS Cohort Study. Am J Psychiatry 1996;1531430- 1437
PubMed
Farinpour  RMiller  ENSatz  P  et al.  Psychosocial risk factors of HIV morbidity and mortality: findings from the Multicenter AIDS Cohort Study (MACS). J Clin Exp Neuropsychol 2003;25654- 670
PubMed Link to Article
Rohling  MLGreen  PAllen  LMIverson  GL Depressive symptoms and neurocognitive test scores in patients passing symptom validity tests. Arch Clin Neuropsychol 2002;17205- 222
PubMed Link to Article
Brew  BJ Markers of AIDS dementia complex: the role of cerebrospinal fluid assays. AIDS 2001;151883- 1884
PubMed Link to Article
Kusdra  LMcGuire  DPulliam  L Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia. AIDS 2002;1631- 38
PubMed Link to Article
Gray  FAdle-Biassette  HChretien  FLorin de la Grandmaison  GForce  GKeohane  C Neuropathology and neurodegeneration in human immunodeficiency virus infection: pathogenesis of HIV-induced lesions of the brain, correlations with HIV-associated disorders and modifications according to treatments. Clin Neuropathol 2001;20146- 155
PubMed
Masliah  EDeTeresa  RMMallory  MEHansen  LA Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 2000;1469- 74
PubMed Link to Article
Neuenburg  JKBrodt  HRHerndier  BG  et al.  HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002;31171- 177
PubMed Link to Article
Detels  RMunoz  AMcFarlane  G  et al.  Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration: Multicenter AIDS Cohort Study Investigators. JAMA 1998;2801497- 1503
PubMed Link to Article
Foudraine  NAHoetelmans  RMLange  JM  et al.  Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine. Lancet 1998;3511547- 1551
PubMed Link to Article
Eggers  CCvan Lunzen  JBuhk  TStellbrink  HJ HIV infection of the central nervous system is characterized by rapid turnover of viral RNA in cerebrospinal fluid. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20259- 264
PubMed Link to Article
Sacktor  NTarwater  PMSkolasky  RL  et al.  CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 2001;57542- 544
PubMed Link to Article
Pardridge  WM Targeting neurotherapeutic agents through the blood-brain barrier. Arch Neurol 2002;5935- 40
PubMed Link to Article
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PubMed Link to Article
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PubMed Link to Article
Letendre  SLLanier  ERMcCutchan  JA Cerebrospinal fluid β chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1. J Infect Dis 1999;180310- 319
PubMed Link to Article
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PubMed Link to Article
Wesselingh  SLTakahashi  KGlass  JDMcArthur  JCGriffin  JWGriffin  DE Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase polymerase chain reaction in situ hybridization and immunohistochemistry. J Neuroimmunol 1997;741- 8
PubMed Link to Article
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PubMed
Munn  DHBree  AGBeall  AC  et al.  Recombinant human macrophage colony-stimulating factor in nonhuman primates: selective expansion of a CD16+ monocyte subset with phenotypic similarity to primate natural killer cells. Blood 1996;881215- 1224
PubMed
Munn  DHGarnick  MBCheung  NK Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates. Blood 1990;752042- 2048
PubMed
Gallo  PPagni  SGiometto  B  et al.  Macrophage-colony stimulating factor (M-CSF) in the cerebrospinal fluid. J Neuroimmunol 1990;29105- 112
PubMed Link to Article
Enting  RHFoudraine  NALange  JM  et al.  Cerebrospinal fluid β2-microglobulin, monocyte chemotactic protein-1, and soluble tumour necrosis factor α receptors before and after treatment with lamivudine plus zidovudine or stavudine. J Neuroimmunol 2000;102216- 221
PubMed Link to Article
Bouwman  FHSkolasky  RHes  D  et al.  Variable progression of HIV-associated dementia. Neurology 1998;501814- 1820
PubMed Link to Article
Dougherty  RHSkolasky  RLMcArthur  JC Progression of HIV-associated dementia treated with HAART. AIDS Read 2002;1269- 74
PubMed
Mocroft  AKatlama  CJohnson  AM  et al.  AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000;356291- 296
PubMed Link to Article
Moore  RDChaisson  RE Natural history of HIV infection in the era of combination antiretroviral therapy. AIDS 1999;131933- 1942
PubMed Link to Article
Ellis  RJMoore  DJChilders  ME  et al.  Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol 2002;59923- 928
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Distribution of plasma human immunodeficiency virus RNA levels based on combination antiretroviral therapy (CART) exposure at the baseline visit. The proportion of patients with high levels of plasma viremia (10 000-100 000 and >100 000 copies/mL) was statistically significantly higher among nonusers of CART. Users of only 1 or 2 antiretrovirals (n = 15) are not displayed.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA levels stratified by American Academy of Neurology (AAN) classification (unimpaired, minor cognitive-motor disorder [MCMD], and HIV-associated dementia [HIV-D]). There were no statistically significant differences in CSF HIV RNA levels using the computerized algorithm to categorize patients. The thick horizontal lines represent mean values; boxes, 25th and 75th percentiles; and error bars, outlier values.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA levels stratified by Memorial Sloan-Kettering (MSK) stage. There were no statistically significant differences in CSF HIV RNA levels using clinical consensus to categorize patients. The thick horizontal lines represent mean values; boxes, 25th and 75th percentiles; and error bars, outlier values.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Distribution of the cohort by neurological status (unimpaired, minor cognitive-motor disorder [MCMD], and human immunodeficiency virus–associated dementia [HIV-D]), stratified by the use of combination antiretroviral therapy (CART) and the presence of high levels of plasma viremia (defined as ≥10 000 copies/mL) at baseline. A greater proportion of nonusers with HIV-D have high-level plasma viremia while a greater porportion of unimpaired CART users have high levels of plasma viremia. Among CART users, there are no significant differences by neurological status.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Baseline Demographic and Clinical Characteristics Across AAN Dementia Classification Categories
Table Graphic Jump LocationTable 2.  Baseline Laboratory Results Across AAN Dementia Classification Categories and Treatment Exposure
Table Graphic Jump LocationTable 3.  Associations Between HIV RNA and Immune Markers and HIV-Associated Dementia
Table Graphic Jump LocationTable 4.  Associations Between HIV RNA and Immune Markers and MCMD/HIV-Associated Dementia Combined
Table Graphic Jump LocationTable 5.  Associations Between HIV RNA and Immune Markers and MSK Stage 1 or Higher

References

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PubMed Link to Article
Zink  MCSuryanarayana  KMankowski  JL  et al.  High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 1999;7310480- 10488
PubMed
Sei  SSaito  KStewart  SK  et al.  Increased human immunodeficiency virus (HIV) type 1 DNA content and quinolinic acid concentration in brain tissues from patients with HIV encephalopathy. J Infect Dis 1995;172638- 647
PubMed Link to Article
Brodt  HRKamps  BSGute  PKnupp  BStaszewski  SHelm  EB Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997;111731- 1738
PubMed Link to Article
Sacktor  NCSkolasky  RLLyles  RHEsposito  DSelnes  OAMcArthur  JC Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors. J Neurovirol 2000;684- 88
PubMed Link to Article
Sacktor  NMcDermott  MPMarder  K  et al.  HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 2002;8136- 142
PubMed Link to Article
Chang  LErnst  TLeonido-Yee  M  et al.  Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 1999;53782- 789
PubMed Link to Article
Sacktor  NCPomper  MGHorska  ABarker  PBMcArthur  JC Magnetic resonance spectroscopic imaging measures metabolite changes during therapy for HIV-associated cognitive impairment [abstract]. Neurology 2000;54A252
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Marra  CMCoombs  RWCollier  AC Changes in CSF and plasma HIV-1 RNA and in neuropsychological test performance after starting HAART.  Paper presented at: Sixth Conference on Retroviruses and Opportunistic infections; February 2, 1999; Chicago, Ill
Deutsch  REllis  RJMcCutchan  JAMarcotte  TDLetendre  SGrant  I AIDS-associated mild neurocognitive impairment is delayed in the era of highly active antiretroviral therapy. AIDS 2001;151898- 1899
PubMed Link to Article
Ellis  RJGamst  ACCapparelli  E  et al.  Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 2000;54927- 936
PubMed Link to Article
De Luca  ACiancio  BCLarussa  D  et al.  Correlates of independent HIV-1 replication in the CNS and of its control by antiretrovirals. Neurology 2002;59342- 347
PubMed Link to Article
Brew  BJHalman  MCatalan  J  et al Abacavir in AIDS dementia complex: efficacy and lessons for future trials. Neurology In press
Fahn  SMarsden  CCaine  D Recent Developments in Parkinson's Disease.  Florham Park, NJ: Macmillan Healthcare Information; 1987
Rey  A L’examen psychologique dans les cas d'encephalopathie traumatique. Arch Psychol (Frankf) 1941;28286- 340
Wechsler  D Wechsler Adult Intelligence Scale Revised.  New York, NY: Psychological Corporation; 1981
Klove  H Clinical neuropsychology. Med Clin North Am 1963;471647- 1658
PubMed
Miller  ENSatz  PVisscher  B Computerized and conventional neuropsychological assessment. Neurology 1991;411608- 1616
PubMed Link to Article
Benton  ALHamsher  KD Multilingual Aphasia Examination.  Iowa City: University of Iowa; 1976
Flowers  KARobertson  C The effect of Parkinson's disease on the ability to maintain a mental set. J Neurol Neurosurg Psychiatry 1985;48517- 529
PubMed Link to Article
Nelson  HEO’Connell  A Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex 1978;14234- 244
PubMed Link to Article
Stern  YAndrews  HPittman  H  et al.  Diagnosis of dementia in a heterogeneous population: development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol 1992;49453- 460
PubMed Link to Article
Dana Consortium on Therapy for HIV Dementia and Related Cognitive Disorders, Clinical confirmation of the American Academy of Neurology algorithm for HIV-1 associated cognitive/motor disorder. Neurology 1996;471247- 1253
PubMed Link to Article
Concha  MSelnes  OAMcArthur  JC  et al.  Normative data for a brief neuropsychological test battery in a cohort of injecting drug users. Int J Addict 1995;30823- 841
PubMed
Lawton  MPBrody  EM Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9179- 186
PubMed Link to Article
Katz  SFord  AMoskowitz  RWJackson  BAJaffe  MW Studies of illness in the aged: the index of ADL. JAMA 1963;185914- 919
PubMed Link to Article
Stewart  ALWare  JE Measuring Function and Well-Being: The Medical Outcomes Study Approach.  Durham, NC: Duke University Press; 1993
Karnofsky  DAAbelman  WHCarver  LF  et al.  The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1948;1634- 656
Link to Article
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed Link to Article
Beck  ATBeamesderfer  A Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry 1974;7151- 169
PubMed
Working Group of the American Academy of Neurology AIDS Task Force, Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type-1 (HIV-1) infection: report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 1991;41778- 785
PubMed Link to Article
Price  RWBrew  BJ The AIDS dementia complex. J Infect Dis 1988;1581079- 1083
PubMed Link to Article
Price  RWSidtis  JJ Evaluation of the AIDS dementia complex in clinical trials. J Acquir Immune Defic Syndr 1990;3(suppl 2)S51- S60
PubMed
Marder  KAlbert  SMMcDermott  MP  et al.  Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment. Neurology 2003;601467- 1473
PubMed Link to Article
Clifford  DBMcArthur  JCSchifitto  G  et al.  A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor impairment. Neurology 2002;591568- 1573
PubMed Link to Article
Centers for Disease Control and Prevention, Cases of HIV infection and AIDS in the United States, 2002. HIV AIDS Surveill Rep 2003;14A1- A7
Lyketsos  CGHoover  DRGuccione  M  et al.  Changes in depressive symptoms as AIDS develops: the Multicenter AIDS Cohort Study. Am J Psychiatry 1996;1531430- 1437
PubMed
Farinpour  RMiller  ENSatz  P  et al.  Psychosocial risk factors of HIV morbidity and mortality: findings from the Multicenter AIDS Cohort Study (MACS). J Clin Exp Neuropsychol 2003;25654- 670
PubMed Link to Article
Rohling  MLGreen  PAllen  LMIverson  GL Depressive symptoms and neurocognitive test scores in patients passing symptom validity tests. Arch Clin Neuropsychol 2002;17205- 222
PubMed Link to Article
Brew  BJ Markers of AIDS dementia complex: the role of cerebrospinal fluid assays. AIDS 2001;151883- 1884
PubMed Link to Article
Kusdra  LMcGuire  DPulliam  L Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia. AIDS 2002;1631- 38
PubMed Link to Article
Gray  FAdle-Biassette  HChretien  FLorin de la Grandmaison  GForce  GKeohane  C Neuropathology and neurodegeneration in human immunodeficiency virus infection: pathogenesis of HIV-induced lesions of the brain, correlations with HIV-associated disorders and modifications according to treatments. Clin Neuropathol 2001;20146- 155
PubMed
Masliah  EDeTeresa  RMMallory  MEHansen  LA Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 2000;1469- 74
PubMed Link to Article
Neuenburg  JKBrodt  HRHerndier  BG  et al.  HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002;31171- 177
PubMed Link to Article
Detels  RMunoz  AMcFarlane  G  et al.  Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration: Multicenter AIDS Cohort Study Investigators. JAMA 1998;2801497- 1503
PubMed Link to Article
Foudraine  NAHoetelmans  RMLange  JM  et al.  Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine. Lancet 1998;3511547- 1551
PubMed Link to Article
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