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Clinical Science

Highly Active Antiretroviral Therapy Improves Neurocognitive Functioning

Robertson, Kevin R. PhD; Robertson, Wendy T. MA; Ford, Sutapa PhD; Watson, David MD; Fiscus, Susan PhD; Harp, Amanda G. BA; Hall, Colin D. MBChB

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2004 - Volume 36 - Issue 1 - p 562-566

Abstract

HIV is known to enter the central nervous system (CNS) within hours or days of initial infection and to remain sequestered in the brain. Many HIV-infected patients develop CNS and peripheral nervous system diseases. The most severe of these is AIDS dementia complex or HIV-associated dementia (HAD). When compared with matched control groups, patients may also have significant but less severe cognitive abnormalities demonstrated by detailed neuropsychological testing. This condition has been labeled minor cognitive motor dysfunction. 1 Treatment with antiretroviral medication may result in improvement in dementia. There have been reports that highly active antiretroviral therapy (HAART) may lead to striking improvement in HAD in individual cases. Administration of HAART also appears to be associated with a decline in the incidence of dementia. However, there are reports of continued progression of HAD despite therapy. Further, with the prolongation in survival associated with more effective viral control, the prevalence of HAD does not appear to be decreasing. HAART results in only very low levels of drug in the CNS, and there is concern that HAART may afford effective systemic treatment but allow continued decline in nervous system function over time. A further concern is that HAART, with its known mitochondrial toxicity, may prove to be neurotoxic over time, leading to progression of nervous system dysfunction despite adequate viral control. To address these concerns, we are conducting a longitudinal evaluation of nervous system performance in a group of subjects before and after the institution of HAART. We report the results of baseline evaluation and 6-month follow-up of these subjects.

METHODS

The University of North Carolina Institutional Review Board approved the study, and all subjects gave informed consent for participation. Subjects were enrolled in the study if they were about to start HAART or if, in the opinion of their infectious disease clinician, their current HAART had failed and they required a different HAART regimen. There was no requirement for or stratification by presence of neurologic disease at study entry. The baseline evaluation was conducted before starting or changing an antiretroviral regimen. Reevaluation was performed after 6 months of stable HAART or when, in the opinion of the treating infectious disease physician, the new regimen failed. At each evaluation, a neurologist conducted a quantified previously validated examination particularly sensitive to the changes found in HIV disease. A neuropsychologist conducted detailed psychological and neuropsychological evaluations that have also been validated as sensitive to the neurocognitive changes found in HIV disease. At each evaluation, subjects also underwent ultrasensitive HIV RNA quantitative evaluation of both plasma and cerebrospinal fluid.

HIV RNA Load

Viral load was assessed through plasma and cerebrospinal fluid measurements. Specimens for viral load and immune functioning were obtained within 8 hours of the neurologic evaluation. Blood and cerebrospinal fluid samples were obtained within 3 hours of each other. Cerebrospinal fluid samples were centrifuged to remove cells. Quantitative HIV-1 RNA load was measured using the Roche Ultrasensitive assay. Neurologic and neuropsychological evaluations were completed in a blinded fashion before viral load analysis.

Neurologic Examination

The AIDS Clinical Trials Group full neurologic evaluation developed by Price and Sidtis was used. This evaluation includes a global assessment of HAD, termed AIDS dementia complex stage, varying from equivocal (0.5) to severe (3.0) dementia. In addition, a quantitative scoring procedure for the neurologic evaluation was implemented, increasing the sensitivity of the instrument and providing domains of functioning. This procedure provides a weighted scoring approach to the items of the neurologic examination and yields an overall neurologic total score as well as scores for cognitive, frontal, pyramidal, extrapyramidal, cranial nerve, cerebellar, spinal, autonomic, sensory, and peripheral domains.

Neuropsychological Evaluation

The neuropsychological evaluation included assessment of the following domains: attention/concentration (2 and 7 test, PASAT), speed of processing (computerized simple and choice reaction time tasks, digit symbol, trailmaking A, stroop word), executive functioning (trailmaking B, stroop color-word, COWA), visuospatial (Rey complex figure copy), verbal memory (RAVLT), figural memory (Rey complex figure immediate, delay), gross motor (timed gait), fine motor (grooved pegboard, finger tapping), and language (WAIS-R Vocabulary).

Memorial Sloan Kettering Dementia Staging

After each visit, the Memorial Sloan Kettering dementia scale was determined for each subject at a consensus conference, utilizing the neurologic and neuropsychological evaluations, the psychiatric interview, and the quality of life scale. The Memorial Sloan Kettering dementia scale is as follows: normal, 0; equivocal (deficits that do not reach the stage of clear dementia), 0.5; and dementia, 1–3 (depending on severity). 1a

RESULTS

Forty-eight subjects were evaluated at baseline before HAART or after one treatment regimen failed and before instituting a different HAART regimen; these subjects then were followed up for 6 months during stable HAART. Only 1 subject was HAART naive at study entry. Thirty subjects (62.5%) were male, and 18 were female (37.5%). Thirty-two subjects (67%) were black, 15 (31%) were white, and 1 was Native American. Twelve subjects (25%) were asymptomatic, 8 (17%) were symptomatic, and 28 (58%) had AIDS according to Centers for Disease Control and Prevention’s criteria (Table 1). Risk factors were primarily homosexual contact (n = 21; 44%), both intravenous drug and sexual transmission (n = 19; 40%), and heterosexual/bisexual transmission (n = 8; 16%). Memorial Sloan Kettering dementia staging revealed that 33 subjects (69%) were normal, 10 (21%) were equivocal, and 5 (10%) were stage 1.

TABLE 1
TABLE 1:
Demographic, Virologic, and Immunologic Variables

All 48 patients were followed up. During Memorial Sloan Kettering dementia evaluation at 6 months, 34 subjects were unchanged, 3 had declined function (2 from 0 to 0.5 and 1 from 0.5 to 1), and 11 had improved function (7 from 0.5 to 0, 3 from 1 to 0, and 1 from 1 to 0.5).

Both plasma (F2,43 = 201.4, P < 0.0001; pretreatment, 4.56 ± 1.4 log copies/mL; during HAART, 2.63 ± 1.8 log copies/mL) and cerebrospinal fluid (F2,37 = 95.6, P < 0.0001; pretreatment, 2.74 ± 1.5 log copies/mL; during HAART, 1.36 ± 1.2 log copies/mL) viral loads declined after treatment (Table 1;Figs. 1, 2). A quantitative scoring procedure was used for the neurologic examination, and summary z scores were calculated for the neuropsychological evaluation. Using a mixed model after 6 months of HAART, significant improvements were found in neurologic scores (F2,47 = 33.86, P < 0.0001; pretreatment, 63.5 ± 65.2; during HAART, 43.02 ± 41.9) (Table 2;Fig. 3). Each individual neurologic domain showed significant improvement (P < 0.01). Neuropsychological scores also significantly improved (F2,47 = 19.63, P < 0.0001; pretreatment, −0.74 ± 0.86; during HAART, −0.52 ± 0.78) (Table 3;Fig. 4). All neuropsychological domains showed significant improvement (P < 0.01) with the exception of gross motor.

TABLE 2
TABLE 2:
Neurologic Functioning by Domain Before and After HAART
TABLE 3
TABLE 3:
Neuropsychological Functioning by Domain Before and After HAART
FIGURE 1.
FIGURE 1.:
Plasma HIV RNA levels before and after HAART.
FIGURE 2.
FIGURE 2.:
Cerebrospinal fluid (CSF) HIV RNA levels before and after HAART.
FIGURE 3.
FIGURE 3.:
Neurologic functioning before and after HAART.
FIGURE 4.
FIGURE 4.:
Neuropsychological functioning before and after HAART.

A concern is that practice effects of repeated testing confounded treatment effects. We addressed this in two ways. Of the 48 subjects, 33 (69%) were naive to prior neurologic and neuropsychological testing, and 15 had been tested in previous studies. To assess whether remote practice effects or prior experience with neurologic assessment confounded the results, we examined differences between subjects who were naive and those who were not. In mixed model analyses with a between-subject factor of naive or not, no significant differences were found between the groups according to the neurologic total score (F1,46 = 0.83, P = not significant; baseline naive [60.6 ± 9.5] vs. experienced [69.8 ± 14.2]). Similarly, no significant differences were found between the groups according to the neuropsychological total score (F1,46 = 0.15, P = not significant; baseline naive [−0.72 ± 0.14] vs. experienced [−0.78 ± 0.21]). Furthermore, no significant differences in interaction between the naive versus experienced groups and treatment over time were found.

In addition, we analyzed HIV-seropositive individuals from a prior longitudinal cohort who were not receiving anti-retroviral therapy but who were evaluated using the same protocols. There was not a significant change over a 6-month period in the neurologic total score (F1,35 = 2.19, P = not significant; 51.09 ± 12.32 vs. 71.99 ± 12.81). The neuropsychological total score (F1,35 = 0.46, P = not significant; −0.20 ± 0.094 vs. −0.27 ± 0.098) indicated that practice effects are not a significant confounding factor in the current study.

DISCUSSION

From the early stages of the HIV epidemic, it has been recognized that the nervous system is involved in the disease process. 2 Early studies suggested that up to 20% of people with end-stage AIDS develop dementia 3 and that up to 95% have evidence of changes during neuropathological examination of the brain. 4 The exact mechanism of this subcortical dementia is not fully understood, because there is no compelling evidence of productive infection of neurons. However, it is known that HIV enters the nervous system in the earliest stages of infection and that there is a population of cells in the CNS, primarily microglia, that remain infected. Therapy with the reverse transcriptase inhibitor zidovudine, the first effective antiretroviral therapy, was shown to have a clear, but temporary, beneficial effect on CNS disease. 5 In the early 1990s, the availability of other reverse transcriptase inhibitors, primarily other nucleoside analogs, was temporally associated with a decline in HAD. In 1992, McArthur 6 reported a 15% incidence of HAD after the diagnosis of AIDS among the Multicenter AIDS Cohort, a closely followed cohort of infected males. With the advent of protease inhibitors, the concept of a “cocktail” of antiretroviral therapies was developed, and such treatments have been classified as HAART. Currently, the optimal cocktail includes at least 3 drugs. It has been established that the resulting reduction in systemic viral burden is an accurate marker of clinical improvement and prolonged life. 7

The effects of HAART on nervous system function are less clear. Epidemiological studies have indicated that there has been a continued decline in the incidence of dementia with more effective therapy. In the Multicenter AIDS Cohort Study, the incidence fell to 7% in the mid-1990s, and preliminary data suggest a further 50% decline since that time. 8 In a retrospective analysis, Maschke et al 9 found a reduction in the prevalence of HAD after 1996. However, with the increased longevity associated with HAART, it is not clear that the prevalence of dementia has declined. 10 A major concern has been that antiretrovirals, particularly the protease inhibitors, achieve satisfactory therapeutic levels in blood and other tissues but have only very low levels of penetration in brain tissue. This raises the possibility that, while systemic illness may be controlled, there may be continuation of or less effective improvement in declining neurologic function. There is evidence of viral sequestration with the development of antiretroviral resistance in the nervous system. 11,12 Pialoux et al 13 also found that the CNS could act as a sanctuary for HIV-1 infection with disease progression despite HAART.

A recent study by Marra et al 14 indicated an improvement in neuropsychological function in a group of 25 subjects after 8 weeks of HAART. However, declining neurologic function continues to be a clinical concern. Dougherty et al 15 analyzed 30 patients with HAD and found that 60% had improved function during HAART and 40% continued to have a decline in function. Dore et al 16 also found some support for the concept that nervous system disease may be less effectively treated than other HIV-related complications. Their review of the Australian experience showed that HAD accounted for 4.4% of AIDS-defining illnesses in 1995 and 6.5% in 1997. In an autopsy series, Neuenburg et al 17 found a rising prevalence of HIV encephalopathy at the time of death. These reports raise the concern that even with HAART there may be a decline in cognitive function as patients live longer. Suggested patterns include initial improvement in dementia after the institution of effective HAART but with a significant residual deficit, slow continued decline in function despite effective peripheral viral control, and initial improvement but then further function decline.

In the current study, there was no indication of function decline in the 6 months after initiation of or change in antiretroviral therapy. On the contrary, there was a robust effect on improving both neurologic and neuropsychological performance. These results suggest that, despite the very restricted access of many antiretrovirals to the nervous system, they are at least initially effective in improving nervous system function.

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