Antivir Ther. 2013;18(2):153-60.

Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected patients with controlled plasma viraemia.

Ciccarelli Nicoletta1; Fabbiani Massimiliano1; Colafigli Manuela1*; Trecarichi Enrico Maria1; Maria Caterina Silveri3; Cauda Roberto1; Murri Rita1; De Luca Andrea2; Di Giambenedetto Simona1.

1Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.

2University Division of Infectious Diseases, Siena University Hospital, Siena, Italy.

3 Memory Clinic, Catholic University of the Sacred Heart, Rome, Italy.

*Corresponding author:



Objectives: Objective of our study was to compare two different Central Nervous System penetration-effectiveness (CPE) scores for the prediction of cognitive dysfunction in HIV-infected patients.

Methods: We performed a cross-sectional single cohort study, consecutively enrolling during routine outpatient visits HIV-infected subjects on antiretroviral therapy with plasma HIV-RNA<50copies/mL. A neuropsychological battery was administered. Each patient was classified as cognitively impaired on the basis of results obtained in age, gender, education and nationality-matched healthy HIV-negative subjects. Self-reported adherence was measured on a 0-100 visual analogue scale. CPE-rank was calculated for each antiretroviral regimen based on rules proposed by CHARTER group in the 2008 original version (orCPE-rank) and the 2010 revised version (revCPE-rank). Neuroeffectiveness categories were analysed based on cut-offs of ≥1.5 (orCPE-rank) or ≥6 (revCPE-rank).

Results: A total of 101 patients were enrolled (66% male; median age 47 years; median education 13 years). Mean adherence was 81%; orCPE-rank≥1.5 and revCPE-rank≥6 were observed in 85% and 78.2% of patients, respectively (p=0.31). Asymptomatic Neurocognitive Impairment (ANI) was diagnosed in 50 (49.5%) subjects. In a multivariable model, after adjusting for nationality, adherence and nadir CD4, orCPE-rank did not show an association with cognitive performance (p=0.704); on the other hand, patients with revCPE-rank ≥6 (OR 0.32, 95% CI 0.11-0.95, p=0.039) and adherence ≥80% (OR 0.39, 95% CI 0.15-0.99, p=0.047) showed a decreased risk of cognitive impairment.

Conclusions: A high prevalence of ANI was observed in virologically suppressed HIV-infected individuals. The revCPE-rank showed improved association with neurocognitive dysfunction over the orCPE-rank. Moreover, a relationship between cognitive impairment and adherence was found.



The importance of neuropenetration of antiretroviral drugs for the prevention of neurocognitive disorders in HIV-infected patients is increasingly recognized.

We performed a cross-sectional study in a cohort of patients on antiretroviral therapy with plasma HIV-RNA <50 copies/mL. Patients were excluded if their age was lower than 18 years or in case of active or known past Central Nervous System (CNS) opportunistic infections, history of neurologic disorders, active psychiatric disorders, alcoholism or drug abuse, decompensated liver disease or cirrhosis, and linguistic difficulties for non-native patients.

All patients underwent a comprehensive neuropsychological battery. Moreover, self-reported adherence was measured on a 0-100 visual analogue scale using a previously validated questionnaire [1]. We selected also an age, gender, education and nationality-matched control population (30 subjects, 19 men and 11 women) who received the same full neuropsychological examination. According to standard criteria [2], cognitive disorders were classified into three categories on the basis of their increased severity: Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorders (MND) and HIV-Associated Dementia (HAD).

CPE-rank was calculated for each cART regimen according to two definitions: (a) orCPE-rank: based on rules proposed in the 2008 original version [3]; regimens were considered as effective for the treatment of CNS infection if orCPE-rank was ≥1.5, which was used as cut-off in previous studies [3]; (b) revCPE-rank: based on 2010 revised version [4]; regimens were considered as effective for the treatment of CNS infection if  revCPE-rank was ≥6, which was the median value in our population and, moreover, a previous study indicated a cut-off of ≥6 as highly predictive of  CSF viral suppression [5].

One hundred and one HIV-infected patients were enrolled (66% male; median age 47 years; 8% non Italian born; 18% past injecting drugs users; 23% had past AIDS-defining events; 23% were HCV co-infected; median CD4 count 620 cells/µL; median CD4 count at nadir 171 cells/µL; median time on antiretroviral therapy 10 years). Median orCPE-rank and revCPE-rank were 1.5 and 6 respectively; orCPE-rank≥1.5 and revCPE-rank≥6 were observed in 81.1% and 78.2% of patients, respectively (p=0.31). Despite virological suppression at the time of the evaluation, only 64/101 (63.4%) patients self-reported an adherence ≥80%.

Overall, 50 (49.5%) patients were classified as cognitively impaired. All showed a profile of ANI and none revealed a cognitive profile of MND or HAD. Overall, patients performed below the cut-off on a higher number of tasks than control subjects [mean 2.94 (SD 2.99) versus mean 1.33 (SD 0.84), p<0.001]. In HIV-infected patients, a lower proportion of ANI was observed when cART regimens with revCPE ≥6 were prescribed (44% versus 68%, p=0.048). On the contrary, no differences were observed when comparing regimen with orCPE above or below 1.5 (50% versus 47%, p=0.812).

Factors associated with ANI were identified by univariate and multivariate logistic regression analysis (Table 1). At univariate analysis, revCPE≥6 showed a nearly significant trend toward a negative association with ANI [odds ratio (OR) 0.37, 95% confidence intervals (CI) 0.14-1.01), p=0.052] while no relationship was demonstrated for orCPE (OR 1.14, 95% CI 0.38-3-43, p=0.812). Among the other variables, an adherence ≥80% emerged as significant protective factors  (OR 0.40, 95% CI 0.17-0.92, p=0.032) while a trend toward an association was observed for non Italian nationality (p=0.054) and a nadir CD4 cell count above 350 cells/µL (p=0.067 when compared to a nadir CD4 cell count lower than 200 cells/μL). In order to test the potential association with ANI of the two CPE versions, we performed two sets of multivariate analyses in which the orCPE or the revCPE were each adjusted for variables showing a trend (p<0.075) towards an association with cognition in univariate analysis. A relationship with ANI could not be demonstrated for orCPE (OR= 0.77, 95% CI 0.21-2.91, p=0.70, after adjusting for nadir CD4 cell count, non-Italian born status, and adherence ≥80%). Conversely, a revCPE-rank ≥6 [adjusted OR (aOR) 0.32; 95% CI 0.11-0.95; p=0.039] showed an independent association with a reduced odd of ANI. Moreover, in this model also an adherence ≥80% (aOR 0.39; 95% CI 0.15-0.99; p=0.047) showed an independent negative association with ANI.

In summary, in our study a high prevalence (49.5%) of ANI was observed, in line with previous findings from other cohorts [6,7]. Although executive functions and memory abilities were confirmed as the most vulnerable functions in HIV-infected patients [7], the deficit was not confined to these cognitive domains and resulted as an extensive asymptomatic cognitive impairment. The main finding was the demonstration of an independent association between revCPE-rank ≥6 and a better neurocognitive performance, while no association was observed for the orCPE-rank. This observation is in line with the evidence of a stronger correlation between CSF viral load suppression and revCPE-rank when compared to the orCPE-rank [4]. Our results suggest that targeting cART regimens on the basis of optimal revCPE rather than orCPE, could represent an improvement for the treatment of HAND.

According to previous studies [8,9] we also found evidence of a relationship between  adherence and neurocognitive performance; in particular, a strong association between a level of adherence ≥80% and a better memory performance was demonstrated. Adherence and cognitive function are likely to be reciprocally related [9],because it is plausible that cognitive disorders, especially memory impairment [10,11], might lead to a decline in adherence to cART and, on the other hand, a poor adherence might contribute to a rebound of viral replication in CNS with development of cognitive impairment.

In conclusion, the neuroeffectiveness of cART regimens largely depends on drug penetration and on the consistency with which the medications are taken. Our study is important because shows that the revCPE-rank represents a step forward in estimating the penetration of antiretroviral drugs in the CNS. Moreover, our data confirmed the importance of a good adherence in order to prevent cognitive disorders. Longitudinal investigations and routine neuropsychological examinations are warranted to better understand the dynamics of the relationship between adherence, neuroeffectiveness of antiretroviral drugs and cognitive impairment.

Table 1 Factors associated to Asymptomatic Neurocognitive Impairment.

tab1Abbreviations:  CI, confidence intervals; HCV, hepatitis C virus; cART, combined antiretroviral therapy; CPE, Central Nervous System Penetration Effectiveness


Acknowledgements: This research was supported by an unrestricted grant from Abbott Virology. The funding sources had no role in the study design, conduct or analyses, and were not involved in the decision to submit the manuscript for publication.



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