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Keywords:

  • antiretroviral therapy;
  • central nervous system penetration effectiveness (CPE) score;
  • cognition;
  • HIV

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objectives

Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals.

Methods

We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients.

Results

Patients were divided into three similarly sized groups (CPE ≤ 1, CPE between 1.5 and 2.5, and CPE ≥ 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients.

Conclusion

These results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Neurocognitive impairment was described in HIV-infected patients prior to the introduction of antiretroviral therapy (ART). At that time, several studies showed that HIV RNA levels in cerebrospinal fluid (CSF) correlated with the severity of HIV-associated dementia [1, 2]. The advent of ART led to undetectability of plasma virus load in about 80% of treated patients, together with a dramatic decrease in the incidence of HIV-associated dementia [3]. However, neurocognitive impairment still occurs, even in patients with blood CD4 counts within the normal range and undetectable plasma and CSF viral load [4]. Cognitive function is a real concern in long-term treated HIV-positive patients because cognitive decline has been linked to all-cause mortality.

Several studies have demonstrated that ART regimens with high central nervous system penetration effectiveness (CPE) ranks improved neurocognitive functioning, but others have reported the opposite finding [5-7], while two recent studies detected neither positive nor negative effects of ART on cognition [8, 9]. The effects of ART on neurocognition are still questionable. Furthermore, because of the multiplicity of new therapies available, the wish to reduce side effects and to simplify ART, and virus resistance, affected patients often do not stay on the same treatment for long periods. Consequently, little is known about effects on cognition after several years of ART with stable CPE scores.

To explore the link between cognitive performance and CPE score after 4 to 7 years of ART with a stable CPE score, we carried out a cross-sectional study exploring neurocognition in HIV-infected patients [10]. The secondary objective was to correlate cognition changes with various classes of treatment.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients were selected from a database of patients followed in the Department of Internal Medicine at Lariboisière Hospital (Paris, France). For this study, a homogenous group of patients with stable CPE scores were selected from this clinical cohort, who initiated ART between June 2003 and December 2006. After the screening, we selected patients according to our inclusion criteria, which were [1]: patients who continued to receive their first treatment unchanged during this period or who switched only once to a new treatment with the same CPE score [2]; individuals who spoke French fluently. To focus the analysis on the influence of CPE in HIV-1-infected individuals, we excluded other factors that may cause cognitive decline or bias its evaluation: we excluded HIV-2 infection, inability to perform neurocognitive tests, current or past opportunistic CNS infections, other neurological or psychiatric disorders, the use of illicit drugs, alcohol abuse, incomplete adherence, coinfection (hepatitis or syphilis) or all other causes that could lead to neurocognitive impairment. Selected patients were split into two groups: included patients and missed-visit patients (patients who did not attend the visit). We compared the two groups to ensure that there were no significant differences between them. All included patients gave their written informed consent to participate in the study.

All included patients underwent a neuropsychological battery. First, to exclude other causes of dementia in older patients and to ensure that a homogenous battery was used, we performed a mini mental test examination [11] in all patients. Secondly, with a short cognitive battery we explored executive functions {using the Frontal Assessment Battery (FAB) [12], clock drawing test [13], 5 words test for memory [14]} and praxis (using the praxis ability scale [15]). Neuropscyhological evaluations were conducted by one trained and certified neuropsychologist. All tests were performed and their results reported according to the standardized procedure.

CPE scores were calculated for each patient as previously described [16] for each antiretroviral drug in the combination, a score of 1 indicating very high penetration, 0.5 intermediate penetration and 0 low penetration. Included patients were divided into groups according to the CPE tertile distribution: group 1, CPE score ≤1; group 2, CPE score from 1 to 2.5; group 3, CPE score ≥2.5. The characteristics of the three groups were compared using analysis of variance for the continuous variable (CPE score) and the χ2 test for categorical variables. For the primary purpose of the study, i.e. to investigate the link between cognition and CPE score, generalized linear models were used. As our secondary objective, we studied the effects of different drug classes (protease inhibitors compared with nonnucleosidic reverse transcriptase inhibitors) and different individual drugs on cognition. Statistical analyses were performed with sas (SAS Institute, Cary, NC); P-values were two-sided.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Of 400 HIV-1-infected patients who initiated ART between June 2003 and December 2006, a total of 307 did not meet our inclusion criteria (280 because their CPE scores were variable, and 27 because they had other causes of cognitive decline). Of the 93 patients who met the inclusion criteria, 39 were in the missed-visit group and the remaining 54 patients were tested.

There was no statistically significant difference between the missed-visit group and the included group for demographic data, Centers for Disease Control and Prevention (CDC) stage, CPE rank, CD4 cell count, duration of HIV infection or duration of treatment.

Participants' characteristics are presented overall and by tertile of CPE score in Table 1. No statistically significant differences were observed among the three CPE tertile groups for demographic data, CDC stage, CPE rank, duration of HIV infection or duration of treatment.

Table 1. Demographic data for patients included in the study and results of linear regression analysis for the relationship between the results of neuropsychological tests and central nervous system penetration effectiveness (CPE) scores in the three groupsa
Characteristic CPE score
Overall (n = 54)1 (n = 14)1.5–2 (n = 18)2.5 (n = 22)P-valueb
  1. FAB, frontal assessment battery; SD, standard deviation.

  2. a

    Group 1, CPE score ≤1; group 2, CPE score from 1 to 2.5; group 3, CPE score ≥2.5.

  3. b

    χ2 test or analysis of variance.

Age (years) [mean (SD)]41.7 (11.1)40.4 (13.9)40.8 (7.6)43.2 (12.0)0.72
Female gender [n (%)]19 (35)8 (57)4 (22)7 (32)0.11
Duration of disease (years) [mean (SD)]7.3 (11.4)5.3 (2.4)5.8 (2.5)9.8 (17.6)0.42
CD4 count (cells/μL) [mean (SD)]460.4 (192.9)544.1 (215.2)372.2 (158.9)479.4 (182.0)0.04
Years of education [mean (SD)]10.1 (3.7)11.0 (3.6)10.2 (4.8)9.5 (2.7)0.52
FAB [mean (SD)]15.2 (3.1)16.6 (1.3)15.1 (3.1)14.4 (3.6)0.045

Figure 1 presents the linear regression analysis for the relationship between the executive function results and CPE scores in the three groups. In the unadjusted model, an inverse relationship was found between CPE score group and FAB results. These findings were still significant after adjustment for age, sex, CD4 count and duration of HIV-1-positive testing (Fig. 1). We did not found any significant correlation with the results of other neuropsychological tests. No association was found between CD4 cell count and neurocognitive performance. There was no difference according to the class of the third component used (protease inhibitor vs. nonnucleoside reverse transcriptase inhibitor). No specific drug or combination of drugs was found to be responsible for this relationship between FAB and CPE score (data not shown).

figure

Figure 1. Box plot for the results of the frontal assessment battery according to central nervous system penetration effectiveness (CPE) scores in the three groups. The linear regression model was adjusted for age and sex. SE, standard error.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

In a homogenous cohort of HIV-1-infected individuals after several years of ART with stable CPE score, we found an inverse relationship between executive functions and CPE score. After adjustment for age, sex, CD4 count and duration of HIV-1 infection, this finding was confirmed. There was no significant relationship between the results of other tests and CPE score or between cognition and specific drugs or combinations of drugs.

As neurocognitive evaluation is an area of great importance in treating HIV-positive patients over the long term, the major point of our study is the cognitive evaluation of patients in a clinical cohort of HIV-infected individuals after several years of ART without any change of CPE scores. Consequently, individual steady-state CSF and plasma RNA levels could thus be expected at the time of cognitive testing. In absence of variations in CSF and plasma, we suggest that cognitive results of all patients are due to ART. We can suppose that ART with high CPE scores could have more side effects or fewer efficacy on brain HIV replication.

Two previous studies explored cognition in patients on ART with stable CPE scores. First, in a large cohort, Smurzynski et al. reported better cognitive performances in patients with high CPE scores taking regimens that contained more than three drugs but not in those taking regimens that contained three or fewer drugs [16]. A comparison with our results is difficult because all the patients included in our study were on regimens containing three drugs. In addition, their population was very heterogeneous in terms of ART type and duration, HIV stages, and comorbidities, while our cohort was more homogenous for the same characteristics. The second work by Garvey et al. detected neither positive nor negative effects of CPE score on cognition [9]. However, the patients in their study had been treated for only 3 months, and it is therefore very difficult to compare our studies because of the difference in treatment duration. Taking the findings of these two studies and ours together, we could hypothesize that treatment duration and the number of drugs in a regimen may affect neurocognitive performance.

Our results are concordant with those of one previous study [7], in which the authors reported that ART with high CPE scores was associated with poorer neurocognitive performance, although it was more effective in controlling CSF viral replication. Taken together, these results and those of our study suggest that ART may have side effects on cognitive functions independently of CSF viral replication. However, in the present study, no specific drug or drug combination seemed to be responsible for the worsening of executive functions.

The problem of cognitive decline seems to be completely different in the treatment-naïve HIV-infected population, in which Cysique et al. and Winston et al. have recently shown a greater cognitive improvement associated with ART with high CPE scores [17, 18]. These studies confirmed the neurocognitive benefit of ART initiation in untreated patients and emphasized the importance of high CPE score at the initiation of ART. They suggest that cognitive impairment could be linked to viral replication in the brain. Nevertheless, the problem is more complex in long-term treated patients who may develop brain lesions. A recent report revealed that CNS injury was evident in persons infected with HIV despite effective ART [19]. This suggests that cognitive effects may be a result of viral replication, ART side effects, and the toxic consequences of active microglia. Further studies, in larger cohorts of patients and with CSF analysis and imaging, will be needed to determine if ART drugs that cross the blood–brain barrier more easily have more cerebral side effects or lower antiretroviral efficacy than other drugs, and if this is linked to virus type and/or individual genetic susceptibility.

Some limitations of our study must be considered. Firstly, cognitive assessments were not performed at baseline, and so we cannot exclude the possibility that cognitive performances were already low at entry into the study. Secondly, as our objective was not to explain the reasons for cognitive alteration, we did not investigate CSF HIV RNA and vascular risks. Thirdly, because it is not easy to find patients with stable CPE scores for several years and no other cause of cognitive impairment, our cohort was small, and not adaptated to multivariate analysis (education level, vascular risk, etc.). This small number of patients could explain the absence of effects of specific drugs or drug combinations on cognition.

In conclusion, we found an inverse relationship between CPE score and cognitive function. We could hypothesize that cognition may be affected by ART. However, conflicting findings were obtained in previous studies. Regardless of CPE score, our data show that specific drugs or drug combinations did not affect cognition. The absence of a clear association may be attributable to the low number of patients. Possible explanations of these results are that the influence of CPE score may be attributable to another unknown confounding factor or may not be as important as previously suggested. Our findings should be interpreted with caution, and further work with larger cohorts is warranted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We thank the Cognivih Study Group (Esma Badsi, Marc Bendenoun, Jeanine Cervoni, Myriam Diemer, Morgane Langlais, Jean-Dominique Magnier, Marie-Christine Mazeron, Stéphane Mouly, François Mouton-Liger, Agathe Rami, Valérie Vincent and Carole Wavrant) for referring patients to our study.

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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