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Nadir CD4 Cell Count Predicts Neurocognitive Impairment in HIV-Infected Patients
Jose A. Munoz-Moreno,1,2 Carmina R. Fumaz,1,2 Maria J. Ferrer,1,2 Anna Prats,1,2 Eugenia Negredo,1,2 Maite Garolera,3 Nuria Perez-Alvarez,1,4 Jose Molto,1,2 Guadalupe Gomez,4 and Bonaventura Clotet1,2,5 1Lluita contra la SIDA Foundation, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Catalonia, Spain. 2Autonoma de Barcelona University, Barcelona, Catalonia, Spain. 3Consorci Sanitari de Terrassa Hospital, Terrassa, Barcelona, Catalonia, Spain. 4Politecnica de Catalunya University, Barcelona, Catalonia, Spain. 5IrsiCaixa Foundation, Badalona, Barcelona, Catalonia, Spain.
See the table below suggesting neurocognitive damage increases incrementally as nadir CD4 increases from 200 to 350, authors suggest starting HAART earlier to protect from neurocognitive damage.... "in the interest of avoiding irreversible neurocognitive impairment, it would probably be wiser to start antiretroviral therapy earlier....
"HAART combinations have been shown to produce improvement of neurocognitive performance, but recent findings have demonstrated that recovery is not achieved in all impaired individuals on therapy.3,5,15,34,35 In fact, failure to improve in this respect has been seen in a significant proportion of patients on HAART.5,14 In our study, indeed, we made the same observation......CD4-related inflammatory changes in the brains of presymptomatic subjects suggested that such alterations may be mediated by the HIV-associated alterations may be mediated by the HIV-associated breakdown of the immune system and consequent lymphocyte dysfunction, allowing brain damage to occur. The authors found evidence for viral replication in the CNS, despite the lack of symptoms in HIV-infected individuals. This finding suggests that neurocognitive functioning is likely to be more affected when more systemic immune suppression appears, a question connected to the main objective of this investigation, and in agreement with our results..... demonstrates the progression of neuronal injury despite the use of antiretroviral therapy, consistent with the observations that we found..... new potential risk factors (such as age, coinfection with HCV, or low educational level"

Though antiretroviral therapy attenuates neurocognitive disruption, impairment is still observed. We studied the nadir CD4 cell count as a predictor of neurocognitive changes. This cross-sectional study assessed 64 HIV-infected patients in two groups: G1 (n =26, nadir CD4200 cells/ml).
Percentages of patients showing neurocognitive impairment were compared according to different nadir CD4 cutoffs (200, 250, 300, and 350 cells/ml). From G2, we also took the subgroup of patients receiving treatment (G3) and compared this group with G1, in which all patients were being treated.
Demographic and clinical variables were evaluated, as were differences in neurocognitive function. Neurocognitive impairment tended to be more prevalent in G1 [19 patients (73.1%)] than in G2 [20 (52.6%), p =0.123].
When nadir CD4 cutoffs were compared, there was a trend toward more impaired subjects as the CD4 nadir decreased. Significantly different functioning was found in attention/working memory (digit span backward, p =0.032) and executive functions (trail making test, part B, p =0.020), with better performance in G2. Comparison between G1 and G3 confirmed those findings.
We found differences in neurocognitive functioning in relation to nadir CD4 count in HIV-infected patients.

Attention should be given to this value in the management of neurocognitive protection in HIV infection.
NEUROCOGNITIVE AND MOTOR IMPAIRMENT may develop in HIV-infected patients. Such impairment is observed in particular in advanced stages of infection, although it may also appear earlier, as has been described in approximately one-third to one-half of asymptomatic HIV-infected individuals.1 Ten years of experience with highly active antiretroviral therapy (HAART) suggests that antiretroviral regimens lead to improvements in cognitive and motor functioning,2-4 although benefits have not been as optimal as expected, and currently deficits persist in a majority of patients despite treatment.5 In addition, though the incidence of the most severe form of impairment, HIV-related dementia, has decreased, its prevalence has remained unchanged.6,7 This maintenance in prevalence has been related to additional new potential risk factors, such as coinfection with hepatitis C virus (HCV) or older age.7 Consistent with those observations are neuropathologic findings indicating that the characteristics of HIV-related dementia are still present and tend to increase in the HAART era.8
The nadir, or lowest, CD4 cell count has been associated with certain HIV-related disruptions such as symptomatic distal sensory polyneuropathy,9 chronic renal failure,10 altered metabolism,11 AIDS-related non-Hodgkin lymphoma, 12 and lipodystrophy syndrome.13 In the case of HIV-related neurocognitive functioning, this nadir count has recently been proposed as a predictor of risk of developing cognitive impairment,7,14,15 although its value as such remains to be studied in depth. The present study assessed the utility of the nadir CD4 cell count as a predictive marker of impaired cognitive and motor functioning in the HIV-infected population. We evaluated the proportion of impaired patients presenting different nadir cell counts, and also studied the differences in neurocognitive and motor functions in accordance with those counts.
Consistent with the conclusions from recent studies,7,14,15 we provide evidence supporting the utility of the nadir CD4 cell count as a predictive marker of risk of neurocognitive impairment in the HIV population. The percentages of neurocognitively impaired HIV-infected patients tended to be higher in the group with a nadir count <200 cells/ml and, confirming that observation, differences in affected neurocognitive domains were also observed.
In our study, the comparison of patients showing neurocognitive impairment according to different CD4 nadir cut points revealed a tendency for a higher prevalence of such impairment at lower nadir counts. The differences between cut points did not reach statistical significance, although the trend found suggested that the highest cut point of 350 cells/ml predicted neurocognitive protection better than the lowest cut point of 200 cells/ml. A link may exist between this finding and other clinical conditions that have revealed the importance of the CD4 nadir as a marker of possible irreversibility, such as the difficulty of immune restoration in individuals with low nadir counts32 or the relationship between nadir CD4 count and physical dysfunction.9-13 In our study, the possible importance of nadir CD4 cell count values involved central nervous system (CNS) functioning. Recently, McCrossan and colleagues33 found CD4-related inflammatory changes in the brains of presymptomatic subjects. They suggested that such alterations may be mediated by the HIV-associated breakdown of the immune system and consequent lymphocyte dysfunction, allowing brain damage to occur. The authors found evidence for viral replication in the CNS, despite the lack of symptoms in HIV-infected individuals. This finding suggests that neurocognitive functioning is likely to be more affected when more systemic immune suppression appears, a question connected to the main objective of this investigation, and in agreement with our results.
Additionally, our findings are also relevant to the question of whether current HAART regimens confer sufficient benefits on neurocognitive functioning, an issue that is currently under debate. HAART combinations have been shown to produce improvement of neurocognitive performance, but recent findings have demonstrated that recovery is not achieved in all impaired individuals on therapy.3,5,15,34,35 In fact, failure to improve in this respect has been seen in a significant proportion of patients on HAART.5,14 In our study, indeed, we made the same observation, detecting altered neurocognitive functioning in 60.9% of the total sample and in 52.6% of subjects presenting with a nadir count >200 cells/ml.

Some authors have suggested the existence of new potential risk factors (such as age, coinfection with HCV, or low educational level 36-38) as a comprehensive explanation for this persistence. In our investigation most of these factors were homogeneously distributed between groups, and we were therefore unable to assess their possible influence. Other authors have hypothesized a burnout effect, leading to mechanisms induced by neuronal death.39,40 According to this hypothesis, irreversible CNS injury would underlie HIV-related neurocognitive impairment, and this would explain the persistence of the current neurologic disruption. Other studies have also observed detectable levels of HIV in cerebrospinal fluid (CSF) in spite of the presence of HAART and virologic success in controlling the plasma viral replication. 34,41,42 Moreover, Arendt and colleagues43 recently showed that viral load in CSF and inflammatory reactions may be suppressed in patients treated with HAART in the early stages of infection, although they also observed that the intrathecal activity of the virus persisted in subjects on therapy who started treatment at later stages. In our opinion, this demonstrates the progression of neuronal injury despite the use of antiretroviral therapy, consistent with the observations that we found.
When we used a cutoff of 200 cells/ml to compare scores of neurocognitive and motor functions, statistical differences were found in two of the domains considered: attention/working memory and executive functions. Individuals with a higher CD4 nadir count showed significantly better functioning in these areas. Both attention/working memory and executive functioning have certainly been two of the domains usually seen to change in people living with HIV.20 In fact, recent studies have confirmed that markers of CNS injury, specifically involving gliosis, are more evident in basal ganglia and frontal white matter, both regions related to these cognitive processes.44 The same markers have been found to be related to motor function, although in our investigation this was not observed, possibly because of our small sample size.
The limitations of our research design should be taken into account. First, there is no accurate way to classify individuals as neurocognitively impaired. We applied the classification method suggested by Tozzi and colleagues,5 but other procedures have also been used. Neurocognitive testing requires the use of comprehensive tools to assess neurocognitive functioning. We therefore used a battery of instruments commonly used in HIV infection research, although other tests have been similarly applied.1-4,6,35-38,43 Second, the use of analyses of multiple comparisons in the same study population could favor a trend in statistical outcomes, similar to the ones we observed. Finally, it should also be considered that the reduced study sample and the design based on a cross-sectional study possibly limited the reliability of the data found.
In summary, our findings reveal an association between a low nadir CD4 cell count and neurocognitive impairment in HIV-infected individuals. Patients with nadir CD4 cell counts <200 cells/ml showed a higher prevalence of neurocognitive impairment as well as decreased functioning in some neurocognitive areas, specifically attention/working memory and executive function. Given that the nadir CD4 cell count, independently of the presence or absence of antiretroviral therapy, may therefore be considered as a predictive risk factor for greater HIV-related neurocognitive impairment, these results may argue in favor of reconsidering the time HAART should be initiated. Currently, international guidelines45 recommend that therapy must necessarily be started when the CD4 nadir reaches <200 cells/ml and that at counts between 200 and 350 cells/ml initiating therapy need only be considered, in accordance with virologic and clinical outcomes. However, as other investigators have recommended, 3,5,14,35,43 and in the interest of avoiding irreversible neurocognitive impairment, it would probably be wiser to start antiretroviral therapy earlier.
Materials and Methods
Study design and participants

An observational, comparative, cross-sectional study was designed to determine associations between the nadir CD4 cell count and neurocognitive and motor functioning in HIV-infected patients. The Centers for Disease Control (CDC) classification16 was followed in assembling the study groups. Thus, based on nadir CD4 cell count value, two main groups were formed as follows: group 1 (G1) consisted of patients with a nadir CD4 count <200 cells/ml and group 2 (G2) consisted of patients with a nadir CD4 count >200 cells/ml.
Our overall objective was divided into three specific aims:
1. To assess whether a nadir CD4 200 cells/ml.
2. To determine whether another nadir count may better predict neurocognitive functioning in HIV-infected patients. In this case, the percentages of impaired individuals were compared in terms of the following different nadir cell count cutoffs: 200, 250, 300, and 350 cells/ml.
3. To study the possible associations with nadir CD4 cell count and the pattern of HIV-related neurocognitive dysfunction. Accordingly, seven significant cognitive and motor areas in HIV infection were compared between individuals with a nadir cell count of <200 cells/ml and individuals with a nadir cell count of >200 cells/ml.
As the presence of HAART was not considered in the primary distribution of study groups, all patients in G1 were receiving antiretroviral treatment although not all patients in G2 were. For this reason an additional classification was created to form a third study group (subgroup G3) composed of those subjects from G2 who were on therapy. Percentages of patients showing neurocognitive impairment, and performance on cognitive and motor areas, were then compared between subgroups G1 and G3. This allowed us to explore the relevance of the presence or absence of therapy on the utility of the nadir CD4 count to predict risk.
The research ethics committee of the Germans Trias i Pujol University Hospital approved the study. Patients were then recruited from among those being treated at the HIV outpatient clinic of the hospital, which is located on the outskirts of Barcelona, Spain. All participants were aged 18 years old and presented a current CD4 cell count 200 cells/ml at the time of enrollment.
We excluded those patients with a prior or current diagnosis of an opportunistic infection involving the central nervous system (CNS), patients with a prior or current diagnosis of a psychiatric disorder, and patients reporting current drug consumption or methadone treatment. After patient recruitment, data were collected during a medical check-up.
The recruitment period lasted 1 year.
Measures and instruments

Demographic, clinical, and emotional variables related to HIV infection or with a possible impact on neurocognitive assessment were recorded. The following variables were collected: age, gender, infection route, years of education, number of individuals receiving HAART, time since HIV diagnosis, time on treatment, current CD4 cell count, viral load, and HCV coinfection.
Emotional status was also assessed in terms of depression and anxiety. Depression was assessed with the Beck Depression Inventory (BDI),17 specifically the cognitive-affective subscale for avoiding biases related to somatic symptoms. 18 Anxiety was evaluated with the State-Trait Anxiety Inventory (STAI),19 a widely used tool in clinical research in the setting of HIV infection.
Seven cognitive and motor ability domains were assessed with a neurocognitive test battery. Its composition focused on the assessment of the more significant areas affecting neurocognitive impairment in HIV-infected patients.20 The tests were as follows: the Wechsler Adult Intelligence Scale-III (WAIS-III); Letter-Numbers and Digits Tests21 for attention/working memory; the Symbol Digit Modalities Test22 and Trail Making Test (TMT) Part A23 for information processing speed; the California Verbal Learning Test24 for verbal memory and learning; the TMT Part B,23 the Stroop Test,25 and the Wisconsin Card Sorting Test26 for executive functions; the Controlled Oral Word Association Test27 and Animals Test28 for verbal fluency; the Electronic Tapping Test29 and Grooved Pegboard Test30 for motor function; and the WAIS-III Vocabulary Test21 for premorbid intelligence. T-scores were calculated to facilitate obtaining percentages of neurocognitively impaired subjects. Neurocognitive impairment was defined as performing one standard deviation below the normative mean on at least two tests, or two standard deviations below the normative mean on at least one test. T-scores were also used to compare differences between cognitive and motor areas. Thus, based on the four nadir cutoffs, four comparisons of percentages of patients showing neurocognitive dysfunction were performed; moreover, based on a nadir CD4 count of <200 cells/ml, 17 comparisons of specific neurocognitive tests were performed.
Data analysis
Statistical equivalence between groups was determined by comparing demographic, clinical, and emotional variables. Premorbid intelligence was also included in this analysis.
Analysis of variance was performed when quantitative variables showed a normal distribution (Kolmogorov-Smirnov test, p values >0.05) and nonparametric tests (Kruskal-Wallis) were applied when they were not normally distributed. A x2 test was used to compare categorical variables between groups as well as to assess differences among percentages of neurocognitively impaired patients. A x2 test for trend in proportions was also performed to assess the linear tendency of differences among nadir CD4 cell count cutoffs.
To study the differences related to neurocognitive functions assessed in G1 and G2, t tests were used, with a level of p < 0.05 was considered significant. In addition, a posthoc subanalysis was performed comparing G1 with G3 to determine whether the presence or absence of HAART might affect the predictive power of the nadir CD4 cell count. Unbiased effect size tests (d)31 were also calculated to determine the magnitudes of differences found.
All statistical analyses were executed by SPSS, v.12.0 (SPSS Inc., Chicago, IL) and R, v.2.2.0. (
Ninety-four patients seen in clinical interviews and fulfilling study criteria were informed about the possibility of participating in the study. Only 67 signed the consent form, and 64 finally participated. A total of 26 subjects were included in G1 (nadir CD4 <200 cells/ml) and 38 subjects in G2 (nadir CD4 >200 cells/ml). Table 1 displays the characteristics of the study sample. Statistical equivalence tests indicated significant differences between groups in the median nadir CD4 cell count (absolute value and percentage), as expected, as well as in the number of patients on treatment, the number of patients with undetectable viral load, and viral load count. In G1 all subjects were receiving HAART when examined, while in G2 approximately half (56.2%) were on HAART. Associated with this, 88.4% of the first group and exactly half of the second group had virologically undetectable counts. Additionally, the median (interquartile range) load was higher in G2 [2.1 (1.6-4.5) log10] than in G1 [1.6 (1.6-1.6) log10] (p =0.001). Although the rest of the variables were not distributed completely homogeneously, none of the differences between groups reached statistical significance for these other variables. The CD4 cell count and the scores for depression and anxiety were the characteristics that were most different (Table 1).
When neurocognitive impairment was determined in the study groups, the percentage of impaired patients tended to be higher in G1 than in G2 (73.1% vs. 52.6%), although the difference did not reach statistical significance (p= 0.123). Nor did the comparison between G1 and G3, in the subgroup analysis, show significantly different results (73.1% vs. 50%; p =0.133). When subjects were analyzed using different cutoff points for nadir CD4 cell counts, it was observed that the percentage of patients with neurocognitive impairment decreased when the nadir cutoff increased, from 73.1% impaired for a nadir <200 cells/ml to 57.1% impaired for a nadir <350 cells/ml (Table 2). None of the differences in the comparisons of prevalence reached statistical significance, although when the nadir cutoff was lower, the difference was greater. The x 2 test for linear trend, considering the nadir cutoffs ranging from 0 cells/ml to 350 cells/ml, confirmed this finding, revealing a decrease in the proportion of patients with neurocognitive impairment when the nadir count was higher (p =0.046).
With respect to the cognitive and motor functions assessed in the two groups formed according to the nadir 200 CD4 cell count cutoff, significant differences in the following neurocognitive performance T-scores for functions were observed: digit span backward of the WAIS-III (attention/ working memory), p =0.032, and TMT Part B (executive functions), p =0.020. Table 3 displays the scores and differences by group. Unbiased effect sizes confirmed these results, with medium effect sizes (d range =0.50-0.63) accompanying the group differences. The rest of the neurocognitive measures did not reveal statistical differences between G1 and G2. However, a general trend toward better functioning was found in the higher CD4 cell count group (G2). Only four out of 16 T-scores did not follow that trend. The differences identified in the comparison with G3 were similar. Significant differences were found in the same neurocognitive areas as in the previous comparison: digit span backward of the WAIS-III (attention/working memory), p=0.032, TMT Part B (executive functions), p=0.020, and percentage of errors of the WCST (executive functions), p=0.045.



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