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Cognitive Performance & Neuroactive ART Drugs
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Neuroactive Antiretroviral Drugs Do Not Influence Neurocognitive Performance in Less Advanced HIV-Infected Patients Responding to Highly Active Antiretroviral Therapy
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 41(3) March 2006 pp 332-337
Giancola, Maria Letizia MD; Lorenzini, Patrizia DSc; Balestra, Pietro PsyD; Larussa, Dora MD; Baldini, Francesco MD; Corpolongo, Angela MD; Narciso, Pasquale MD; Bellagamba, Rita MD; Tozzi, Valerio MD; Antinori, Andrea MD
From the Clinical Department, National Institute for Infectious Diseases "Lazzaro Spallanzani," Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
Presented at the 11th Conference on Retroviruses and Opportunistic Infections, 2004, San Francisco.
Abstract
Objective: To analyze the effect of antiretroviral therapy, including drugs that have good penetration in cerebrospinal fluid (CSF), on neuropsychologic performance.
Methods: One hundred sixty-five HIV-1-infected patients exposed to a stable highly active antiretroviral therapy (HAART) regimen were studied. Neuropsychologic examinations were performed for all patients.
Results:
A total of 50.3% of patients were impaired.
In multivariate analysis, older age (for 10-year increase, odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.2 to 10.4; P< 0.0001) and higher plasma HIV-1 RNA levels (OR = 1.90, 95% CI: 1.1 to 3.2; P = 0.021) at testing were independently associated with an increased probability of impaired neurocognitive performance, whereas higher educational level was a protective factor (OR = 0.76, 95% CI: 0.65 to 0.90; P=0.001).
A significant linear correlation was observed between the neuropsychologic z score for 8 tests (NPZ8) score, a quantitative parameter of neurocognitive impairment, and CD4 cell count at neuropsychologic testing (R = 0.273, P = 0.001) and between the NPZ8 score and the patient's age (R = 0.288, P = 0.001).
Conclusions: Our study indicates that the use of stable HAART, including multiple drugs that have good CSF penetration, was not associated with neuropsychologic performance. To prevent independent replication of HIV in CSF with better control of a relevant reservoir of HIV is one of the crucial aims of therapeutic strategy.
BACKGROUND
Cognitive impairment is a common complication in HIV infection, particularly in the late phase of the disease, presenting as a wide spectrum of disorders ranging from mild forms of HIV-associated minor cognitive-motor disorders (MCMDs) to severe forms of cognitive impairment, known as HIV-associated dementia (HAD).1 An accurate clinical evaluation of the patients can be made using a neuropsychologic battery of tests to investigate neurocognitive impairment.2 The level of HIV-1 RNA in cerebrospinal fluid (CSF) as well as in plasma as a biologic marker is an indirect tool used to assess active infection in brain tissue.3 Elevated HIV-1 RNA levels in CSF have been associated with HAD4,5 and have been found in neurocognitively impaired patients with late-stage HIV disease.6 Moreover, high CSF HIV-1 RNA levels predict the subsequent progression to neuropsychologic impairment in HIV-infected patients.7 Highly active antiretroviral therapy (HAART) has been demonstrated to reduce HIV-1 RNA in CSF effectively,8,9 and after the introduction of HAART, the incidence of dementia was significantly lower in HIV-infected patients.10 A recent postmortem neuropathologic series showed an increased incidence of mild to moderate encephalopathy despite HAART,11 however, and temporal trends of prevalence for MCMDs showed a progressive increase with calendar year of the HAART era,12 probably attributable to less severity of clinical disorders and longer survival of HIV-infected patients treated with HAART. Neurocognitive disorders continue to be a relevant function-limiting problem for HIV-infected patients and were related to an increased risk of death.13 The control of HIV-1 RNA in CSF seems to be a crucial issue to avoid the development of HIV-related cognitive syndromes.7
Penetration of antiretroviral drugs in CSF is variable because of the blood-brain barrier; therefore, drugs reach varying concentrations in CSF. Certain antiretroviral drugs (eg, zidovudine, stavudine, lamivudine, abacavir, nevirapine, efavirenz, indinavir) are known to achieve good levels in CSF that effectively control local HIV replication, whereas other drugs penetrate less effectively.14-21 Undetectable drug levels in CSF fail to exclude drug activity in the brain, but in the case of suboptimal drug concentrations, viral replication may continue and promote the selection of resistant mutants22 in the neurologic compartment. Currently, there is no consensus opinion for the best therapeutic strategy for treating CSF HIV infection, and the impact of treatment with CSF-penetrating drugs on HIV-associated neurocognitive impairment in routine practice needs to be more conclusively assessed. The aim of the present study was to analyze the effect of antiretroviral therapy, including drugs that have good penetration in CSF, on neuropsychologic performance of HIV-infected patients who were exposed to a stable HAART regimen.
DISCUSSION
We investigated the efficacy of using neuroactive drugs included in a stable long-term HAART regimen on neurocognitive function in HIV-infected patients. Patients included in the present study presented with a mild degree of immunodeficiency, as confirmed by the high mean CD4 count (476 cells/mm3). Neurocognitively impaired HIV-infected patients presented with a significantly lower CD4 cell count compared with unimpaired patients, but these 2 groups of patients did not differ for plasmatic HIV-1 load and were exposed to the same class of antiretroviral drugs. Nadir CD4 cell count, a known predictive factor of neurocognitive deficit, was significantly lower in impaired patients than in unimpaired patients. Our study indicates that the use of stable HAART containing multiple neuroactive drugs was not associated with impaired or unimpaired neuropsychologic performance as assessed by qualitative and quantitative parameters. Moreover, neither the exposure to a specific class of antiretrovirals nor the use of a specific single drug was associated with the patient's neuropsychologic performance. HIV replication in plasma and older age were the only factors independently associated with neuropsychologic disorders. A quantitative score of neuropsychologic deficit, the NPZ8 score, was significantly correlated with CD4 cell count and patient age but not with the number of neuroactive drugs.
The optimal antiretroviral therapy for HIV-infected patients affected by neurologic disorders is currently unknown. HIV invades the CNS early and continues to replicate indeterminately with different dynamics in the successive stages of infection. 25,26 In clinically stable untreated patients, HIV-1 viral load reaches a dynamic equilibrium and remains stable in CSF around a set point.27 HAART has been known to induce altered patterns of epidemiologic and clinical characteristics for neurologic manifestations in the HIV-infected population. In the HAART era, a marked reduction of a diagnosis of HAD has been observed,10 but a proportionally prevalent increase of these neurologic disorders compared with other initial AIDS-defining illnesses has appeared.28 A higher CD4 cell count at the diagnosis of neurocognitive impairment was also recognized10,28 and MCMDs showed an increasing incidence trend among neurocognitive disorders.12 The benefit of HAART on neuropsychologic function is actually well known,29,30 but the presence of a significant proportion of neurocognitively impaired HIV-infected patients and the persistence of neurocognitive abnormalities after long exposure to HAART are relevant problems in the late HAART era.31 Neurocognitive improvement has been associated with a decline in CSF HIV-1 RNA in HIV-infected patients who started HAART therapy after the diagnosis of a cognitive deficit.32,33 An additional unresolved question concerns the role of neuroactive drugs to promote more effective control of CSF HIV replication and to influence neurocognitive performance. The effect of nucleoside analogues on psychomotor slowing and neurologic performance in HIV-infected persons has been previously reported.24,34,35 More recently, in a large European prospective multicenter observational study (EuroSIDA), the use of nucleoside reverse transcriptase inhibitors seemed to protect specifically against HAD, irrespective of the use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors.36
Clinical observations have also suggested that the use of multiple blood-brain barrier-penetrating drugs effectively decreases HIV-1 RNA levels in the CSF.9,37,38 In fact, in a previous study conducted in HIV-infected patients with marked immunodeficiency and neurologic disorders, including HIV encephalopathy, we showed that a greater reduction of CSF HIV-1 RNA was observed when 3 or more drugs penetrating the blood-brain barrier were used.9 Moreover, it was recently reported that CSF RNA levels at baseline and during follow-up significantly correlated with neurocognitive improvement and confirmed that a higher number of CSF-penetrating antiretrovirals was associated with a greater decrease in CSF viral load.38 In the less advanced HIV-infected population, however, the use of multiple CSF-penetrating drugs did not result in protection from HIV-associated psychomotor slowing compared with single CSF-penetrating HAART,39 whereas the response to systemic HIV-1 viral load suppression correlated with psychomotor speed performance.40 Cysique et al41 recently suggested a threshold of neurologic impairment above which the benefit of using at least 3 neuroactive drugs is observed; however, they failed to reveal a benefit of HAART containing neuroactive drugs in HIV-advanced patients with high current CD4 counts and a low CD4 cell nadir. It is conceivable that in the HIV-infected population with and less advanced disease but mild neurocognitive impairment, multiple CSF-penetrating drugs are not strictly required to control CNS HIV-1 replication. Conversely, in more advanced HIV-infected patients, especially those affected by clinical neurologic disorders, clinicians may consider the use of a higher number of neuroactive drugs to obtain a better virologic response in the CSF compartment and a more favorable impact on neurologic disease.
This clinical aspect could be attributable to the known mechanisms of HIV virion production in the CNS. In the early phases of HIV infection, virions in the CSF come from the plasma and the rapid production is sustained by infected CD4 T cells, characterized by rapid turnover; in the later phases, virus is mainly produced by longer lived cells such as monocytes and macrophages.25,26,42 In the early stages, when immune function is quite preserved and cognitive functions are moderately affected, the control of plasmatic HIV replication could be sufficient to control HIV replication in CSF and the use of multiple CSF-penetrating drugs may not be absolutely required. The significant association between plasma levels of HIV-1 RNA and the presence of neurocognitive impairment recognized in the present study supported the hypothesis that the control of plasma viremia could be sufficient in less advanced HIV patients who are affected by mild neurocognitive disorders. In the later stages of infection, multiple neuroactive drugs could be required to control the local viral replication, the main source of HIV virions in CSF, and to effectively influence the neurocognitive outcome. Also, we found that older age is a factor independently associated with neurocognitive impairment. For the effect of prolonged survival in the aging HIV population, cognitive deficits occur with an increasing prevalence and are becoming an emerging issue. In our study, however, we failed to find an association with HCV coinfection, as other authors have reported.43
This study has several limitations. Unfortunately, measurements of HIV-1 RNA levels in CSF were not available in the study population. Furthermore, because of the unselected characteristic of case records, heterogeneity of drugs and drug combinations used was present in the study population. It is likely that more accurate information could be obtained by analyzing specific multiple associations of antiretrovirals and time of exposure to HAART. One must consider that clinicians might be more likely to prescribe a higher number of neuroactive drugs in marked neurologically symptomatic patients, and this factor could have affected the present study. Moreover, we considered the effect of neuroactive drugs only in the last 6 months before neuropsychologic testing; consequently, we cannot exclude an accumulated effect of CSF-penetrating drug exposure in the overall antiretroviral history. Finally, we used a cross-sectional approach. Prospective data on serial neuropsychologic testing is necessary to assess the direct effect of therapy on neuropsychologic performance definitively. Nevertheless, this study provides more information about an unresolved issue despite the previously mentioned limitations. The best therapeutic strategy to obtain control of the replication of HIV-1 RNA in CSF has yet to be defined, but to prevent an independent replication of HIV in CSF and to control a relevant reservoir of HIV are crucial objectives.44-47 This goal is necessary to avoid the systemic failure of antiretroviral treatment and to prevent neurocognitive impairment of HIV-infected patients. Clinical trials specifically designed to define the effect of combination of antiretrovirals in defined settings should be helpful in providing more information.
METHODS
We performed a cross-sectional study on HIV-infected patients followed at the National Institute for Infectious Diseases "L. Spallanzani" between 1996 and 2003. Patients who were taking the same HAART regimen unchanged for at least 6 months and who underwent neuropsychologic testing were included in this study. Neuropsychologic examination was required when there were symptoms of cognitive impairment, regardless of CD4 count, as well as in cases of severe immunodeficiency (defined as CD4 counts of <200 cells/mm3) in neurologically asymptomatic patients as part of their routine clinical management.
For neuropsychologic testing, a battery of 17 standardized tests was administered by the same neuropsychologist so as to analyze a wide spectrum of different cognitive domains: concentration and speed of mental processing (Trail Making A, Wechsler Adult Intelligence Scale-Revised [WAIS-R] Digit Span [forward and backward], WAIS-R Digit Symbol, Stroop Word and Color, and Corsi Cube test), mental flexibility (Trail Making B, Stroop Color-Word, and Controlled Oral Word), memory (Rey Auditory Verbal Learning, Rey Auditory Verbal Learning after 15 minutes, Rey Complex Figure delayed, and Babcock Story Recall [immediate and delayed]), fine motor functioning (Lafayette Grooved Pegboard [dominant and nondominant]), and visuospatial and constructional (Rey Complex Figure, copy).2 Scores were adjusted for gender, age, and education and were compared with population-based norms. Patients presenting with potential confounders such as alcohol or recent drug abuse events, concomitant neurologic opportunistic HIV-related disorders, other non-HIV-related neurologic illness, or psychiatric disorders were excluded. Depression was excluded by clinical impression; in patients with a clinical impression of possible depression, the Self-Rating Depression Scale according to W.K. Zung was performed to exclude such possible confounders. Patients who met the diagnostic criteria for severe HIV dementia stage III through IV according to Sidtis and Price's classification23 were also excluded. Among antiretroviral drugs that were prescribed, neuroactive drugs were defined as those with high central nervous system (CNS) penetration, presenting effective levels in CSF, or effectively suppressing HIV-1 RNA in CSF. In accordance with literature data, zidovudine, stavudine, lamivudine, abacavir, nevirapine, efavirenz, and indinavir satisfied this definition and were considered as neuroactive drugs for the present study purposes.
Patients were classified as neurocognitively impaired or unimpaired according to their neurocognitive performance, adjusted as described previously. Neurocognitive impairment was defined when more than 1 standard deviation (SD) below the normative mean on 2 tests or more than 2 SDs below the normative mean on 1 test was present. Moreover, the z score was calculated in the following way, as derived from literature24: the raw score for an individual's performance on a single test was converted to a z score by subtracting the reference group mean and dividing the resulting difference by the reference group's SD. The reference population consisted of 346 HIV-seropositive subjects without neurocognitive impairment followed at the same clinical department. Separate reference means and SDs were determined for patients of different ages and educational levels. A summary measure, the neuropsychologic z score (NPZ), was derived by taking an average of the individual z scores for 8 tests (NPZ8). For the NPZ8, the screening battery consisted of Trail Making A and B, Lafayette Grooved Pegboard (dominant and nondominant hands), WAIS-R Digit Span backward, WAIS-R Digit Symbol, Rey Auditory Verbal Learning Test, and Rey Auditory Verbal Learning Test after 15 minutes. HIV-1 RNA levels in plasma were measured by the branched DNA method (Bayer) with a detection limit of 1.69 log10 copies/mL. Blood CD4 cell counts were performed by flow cytometry.
For statistical analyses, we compared the impaired group with the unimpaired group using the ƒÔ2 test for the categoric variables and the Student t test for the continuous variables. Crude and adjusted logistic regression models were used to analyze the predictive factors of neuropsychologic impairment. Linear regression was employed to study the relationships of the NPZ8 score with age, viroimmunologic parameters, and the number of neuroactive drugs. A P value of <0.05 was considered significant.
RESULTS
One hundred sixty-five HIV-infected patients from 1996 to 2003 satisfied the inclusion criteria and were included in the study. The main characteristics of patients at the time of neuropsychologic testing were: male in 72.7% of cases, intravenous drug use in 36.8% of cases, sexual transmission of HIV in 36.4% of patients, and a previous AIDS-defining event in 38.8% of patients; mean patient age was 41 (95% confidence interval [CI]: 39.3 to 41.8) years, mean CD4 cell count was 476 (95% CI: 426 to 526) cells/mm3, nadir of CD4 cell count was 200 (95% CI: 170 to 231) cells/mm3, and mean plasma HIV-1 RNA level was 2.55 log10 (95% CI: 2.38 to 2.71) copies/mL. All patients were HAART experienced and had been exposed to the same HAART regimen for at least 6 months. At the time of neuropsychologic testing, 9.7% of patients received none or 1 CSF-penetrating drug, 32.7% received 2, and 57.8% received 3 or more. In 50.3% of patients, neuropsychologic testing was scored as abnormal: 83 patients presented with neurocognitive impairment, whereas 82 were unimpaired. The characteristics of the 165 patients included in the study according to their neurocognitive profile are reported in Table 1. Neurocognitive impaired patients presented with a previous AIDS-defining event (P = 0.001), a lower CD4 cell count (P < 0.001), and a lower nadir CD4 count (P = 0.01) more often compared with unimpaired patients. No significant difference for gender, age, educational level, AIDS-defining events, CD4 cell count, or plasma HIV-1 RNA level was present among study patients according to the number of CNS-penetrating drugs taken (Table 2). In multivariate analysis, older age (for 10-year increase, OR = 4.8, 95% CI: 2.2 to 10.4; P < 0.0001) and higher plasma HIV-1 RNA levels (OR = 1.90, 95% CI: 1.1 to 3.2; P = 0.021) were independently associated with an increased probability of impaired neurocognitive performance, whereas higher educational level was a protective factor (OR = 0.76, 95% CI: 0.65 to 0.90; P = 0.001).
Neither class of antiretroviral agents nor single or multiple drugs having good CSF penetration were associated with the decreased risk of abnormal neuropsychologic performance. No significant effect on cognitive impairment was observed that correlated with CD4 cell count, previous AIDS-defining events, hepatitis C virus (HCV) coinfection, or hemoglobin levels. When we considered a quantitative parameter, the NPZ8 score, a significant linear correlation was observed between NPZ8 score and CD4 cell count at neuropsychologic testing (R = 0.273, P = 0.001) and between NPZ8 score and patient age (R = 0.288, P = 0.001) (Fig. 1). The NPZ8 score did not show any correlation with plasma HIV-1 RNA load or with the number of CSF-penetrating drugs included in HAART regimen (Fig. 2).
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