Neurocognitive impairment (NCI) is a frequent complication that is reported to affect 30%–60% of HIV-infected patients.1 It has detrimental consequences for quality of life2 and daily functioning3 and has been associated with more complex patient management involving poorer adherence,4 more frequent virological failure,5 and higher mortality rates in individuals with previous mild neurocognitive changes.6
Standard comprehensive neuropsychological test batteries are recommended for the assessment of NCI in HIV-infected patients.7–9 However, these tests provide broad information on neurocognitive functioning rather than useful data on the initial stages of the diagnosis of an HIV-associated neurocognitive disorder (HAND). Thus, brief and sensitive screening methods for the detection of NCI are desirable in clinical practice. Given that access to neuropsychological resources is problematic in many settings, such a screening method should be readily available. In addition, any individual with HIV infection could be at risk of developing HAND; therefore, not only those with more evident suspicion or at high risk should be tested.9 Nonetheless, although several methods to screen for NCI have been proposed, they are difficult to apply in clinical practice.10 There are several reasons for this discrepancy. First, these tools are not traditionally used in HIV infection; therefore, clinical experience is limited. Second, widespread application is affected by copyright restrictions and instrumental requirements. And third, their accuracy for detecting NCI is variable, and they generally present better properties when detecting marked impairment, rather than mild forms of HAND.
Hence, we developed the NEUrocognitive HIV study (NEU), a multicenter investigation aimed at finding a brief, feasible, and sensitive instrument to screen for NCI in HIV-infected patients. After administering a comprehensive neuropsychological test battery including paper-based, computerized, and instrumental tests to a population of HIV-infected outpatients, we compared the accuracy of score combinations enabling the detection of NCI to develop a short paper-based instrument that could prove useful in screening for HAND in routine clinical practice.
Study Design and Population
The NEU study was an observational multicenter investigation whose main sponsor was the Lluita Contra la SIDA Foundation (www.flsida.org).
A total of 7 hospitals in Barcelona, Catalonia, Spain, participated, and the HIV-infected outpatients attended in their respective HIV units were informed about the study as part of the daily routine of the unit. After the invitation to participate, 114 individuals were recruited, and 106 were finally included in the data analyses (8 participants did not complete all the study assessments). The inclusion criteria were age ≥18 years, positive results in an enzyme-linked immunosorbent assay and a confirmatory Western blot, full understanding of the study objectives and procedures, and signed informed consent to participate. The exclusion criteria were incomplete study assessments or voluntary withdrawal from the study. Potential confounding comorbidities for the detection of NCI were not used as exclusion criteria to achieve a more representative sample and to be able to apply relevant information on those conditions in the study analyses. Thus, their existence was controlled and recorded as a clinical study variable. After recruitment, all the participants were scheduled for a new study visit, at which the relevant information was collected.
All the study procedures were conducted in accordance with the 1964 Declaration of Helsinki [fourth revision (1996)] and Good Clinical Practice Guidelines and were approved by the Research Ethics Committee of the Germans Trias i Pujol University Hospital (Project Number: EO-07-039). The NEU study was carried out from April 2008 to December 2011.
Demographic and Clinical Assessments
In addition to neurocognitive variables, we evaluated demographic, clinical, and psychological variables.
Demographic variables included age, gender, route of infection, employment status, and years of education and were obtained by self-report.
Clinical variables comprised current CD4 cell count, nadir CD4 cell count, plasma viral load, highest plasma viral load, being antiretroviral treatment naive, being on antiretroviral treatment, drugs included in the regimen, central nervous system (CNS) penetrance-effectiveness (CPE) score, previous therapy interruptions, time since HIV diagnosis, time since initiation of the first regimen, time on the current regimen, coinfection with hepatitis C virus, and existence of comorbidities potentially affecting neurocognitive performance. This information was extracted from clinical histories and local clinical databases. The CPE score was based on the proposal by Letendre et al in 2010.11 A treatment interruption was defined as any discontinuation of antiretroviral therapy longer than 15 days, regardless of the number of discontinuations, and was recorded based on previous results from our group revealing connections between previous interruptions of therapy and worse neurocognitive status.12 Potential confounding comorbidities for the detection of NCI were similar to those taken into consideration in the Frascati criteria.7 In our work, these conditions were classified as dichotomous variables (yes/no), according to the presence of comorbidity and type of comorbidity. The comorbid conditions included previous or current diagnosis of a psychiatric disorder, current psychopharmacologic therapy, current illegal drug use, and previous or current CNS-related disease.
Psychological variables included emotional status and quality-of-life scales. In emotional status, symptoms of depression and anxiety were monitored and evaluated using the Beck Depression Inventory13 and the State-Trait Anxiety Inventory.14 As for depressive symptoms, the cognitive-affective subscale was used to avoid biases related to somatic symptoms.15 Quality-of-life variables were assessed using the MOS-HIV questionnaire, a self-report tool that examines 9 specific quality-of-life scales and 2 additional global dimensions.16
Neurocognitive variables were assessed using a comprehensive battery of neuropsychological tests covering 7 recommended neurocognitive areas in HIV-infected patients.7–9 The battery comprised 21 tests (13 paper-based, 3 computerized, and 5 instrumental). Application time ranged from 2 to 2.5 hours. The tests used and the areas covered were as follows: the Letter-Numbers and Digits tests of the Wechsler Adult Intelligence Scale-III (WAIS-III)17 for attention/working memory; part A of the Trail Making Test (TMT-A)18 and the Symbol Digit Modalities Test19 for information processing speed; the California Verbal Learning Test–Part II (CVLT-II)20 for verbal memory and learning; part B of the TMT (TMT-B),17 the Stroop Test,21 the Wisconsin Card Sorting Test,22 and the Tower of London Test23 for executive functioning; the Controlled Oral Word Association Test (COWAT)24 and the Animals Test25 for verbal fluency; and the Electronic Tapping Test,26 the Grooved Pegboard Test,27 and the MacQuarrie Test28 for motor function. All tests were used in their Spanish versions. Table 1 describes the characteristics of this battery. Standardized T scores were used for all comparisons. These were obtained after adjusting the raw scores according to Spanish and English available normative data and covering principally age, gender, and educational level.20,22,27,29–36
Besides the above-mentioned tests, the Vocabulary test of the WAIS-III17 was used to examine premorbid intelligence. Self-reported cognitive complaints and interference in daily functioning were also recorded and considered dichotomous categorical variables (yes/no), as reported elsewhere.37
NCI was defined as mild when performance was 1 SD below the normative mean in at least 2 neurocognitive areas and as moderate to severe when performance was more than 2 SDs in at least 2 neurocognitive areas; this approach has been used extensively by other authors assessing NCI in HIV infection.38–42 The Frascati criteria were applied to describe the distribution of HAND in the sample, although only in those individuals with no presence of confounding comorbidities. NCI was classified as asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) according to the severity of the impairment and the presence of interference in daily functioning. Specifically, a patient was considered to have ANI and MND when presented mild impairment and HIV-associated dementia when moderate-to-severe impairment was detected. The differentiation between ANI and MND was established according to the presence of interference in daily functioning.7
Normally distributed variables were described as mean (SD); nonnormally distributed variables were described as median [interquartile range (IQR)]. Categorical variables were described using frequencies and percentages. Variables associated with NCI were described as means and compared using the t test, Mann–Whitney test, χ2 test, or Fisher exact test, again depending on the distribution of the variables. All comparisons were univariate and 2-tailed. Statistical significance was set at P < 0.05. The accuracy of the battery for detecting NCI was assessed in terms of sensitivity and specificity. Positive and negative predictive values were also calculated and reported with their 95% confidence intervals.
Several combinations of scores were compared to better classify participants as having or not having NCI. In this regard, the presence of NCI was considered the gold standard for study comparisons. Because the main objective of this work was to find a brief and feasible tool to screen for NCI in HIV-infected patients, all score combinations were compared to find a paper-based test with an application time of ≤10 minutes. Some of the comparisons included combinations proposed in the literature as potential neurocognitive screening methods.
Once the analysis was completed, additional examinations were performed considering scores based only on paper-based tests with a longer completion time. The main combinations studied were those covering all 7 neurocognitive areas recommended for the assessment of NCI in HIV-infected patients. The combination with the best results was proposed as a reduced neuropsychological battery, rather than as a brief and feasible screening method, owing to the unrestricted time for application and the greater number of neuropsychological tests included.
All statistical analyses were performed using SPSS Statistics, v.15 (SPSS, Chicago, IL) and R, v.2.12 (http://www.r-project.org).
Participants were predominantly men (87%) with a median (IQR) age of 44 years (39–48 years) who were on treatment. Median current CD4 count was 601 cells per microliter (402–791 cells/µL), and median nadir CD4 count was 204 cells per microliter (90–354 cells/µL). The remaining demographic and medical characteristics are displayed in Table 2.
NCI was present in 51 participants (48%), of whom 26 (51%) reported cognitive complaints. The most prevalently affected neurocognitive areas were attention/working memory, information processing speed, and executive functioning, and the measures that showed the lowest mean (SD) T scores: TMT-A total time, 39 (13); TMT-B total time, 38 (16); and percentage of Wisconsin Card Sorting Test errors, 37 (8). The presence of NCI was associated with lower nadir CD4 counts (P < 0.001), being on antiretroviral therapy (P = 0.004), fewer years of education (P = 0.009), and existence of potential confounding comorbidities (P < 0.001). Other variables found in association, although not reaching statistical significance, were female gender (P = 0.06), undetectable viral load (P = 0.06), and time with HIV (P = 0.08). Worse quality of life was also related to NCI, particularly on the physical and role functioning scales (P = 0.01 and 0.002, respectively). When antiretroviral therapy was taken into consideration, 49 participants (53%) had NCI (P = 0.004). No connection was observed with the CPE score, although there was a trend toward greater NCI with lower CPE scores, particularly in those patients with lower nadir CD4 counts and a CPE score higher than 7 (P = 0.14). Potential confounding comorbidities for the detection of NCI were present in 59 individuals (55%), among whom NCI was detected in 38 cases (64%) and cognitive complaints in 39 (66%). The distribution of comorbidities was as follows: 36 (34%) reported previous or current psychiatric disorder, 33 (31%) were receiving psychopharmacologic therapy, 13 (12%) reported illegal drug use, and 14 (13%) had a previous or current CNS-related disease. In patients without comorbidities, NCI was principally related to time with HIV (P = 0.004), antiretroviral treatment (P = 0.01), and undetectable viral load (P = 0.01). Of those individuals, 9 (69%) had ANI and 4 (31%) had MND.
The combinations of neurocognitive scores compared comprised 1–3 measures, according to the maximum time expected for application (ie, 10 minutes). Once the measures were compared, the most accurate selection for detecting NCI, which we called the NEU Screen, comprised TMT-A total time, TMT-B total time, and the COWAT total score. This group of measures presented a sensitivity (95% confidence interval) of 74.5% (60% to 85.2%), specificity of 81.8% (68.6% to 90.4%), positive predictive value of 79.1% (64.1% to 89%), and negative predictive value of 77.5% (64.4% to 87%). Table 3 summarizes the characteristics and properties of the selection. Other combinations of scores that showed similar accuracy comprised 2–3 measures. These were also feasible paper-based combinations, and some of them consisted of other proposed methods to screen for NCI in the HIV-infected population.43,44 The characteristics of some of these combinations are shown in Table 4.
As for the analyses considering groups of measures taking >10 minutes to administer and covering all 7 recommended areas in HIV infection, 1 combination indicated optimal accuracy for detecting NCI. This option included the Letter-Numbers (WAIS-III) total score, TMT-A total time, CVLT-II long-term free recall, CVLT-II total A list, TMT-B total time, COWAT total score, and MacQuarrie nondominant hand score. For this selection, the sensitivity was 100% (91.2% to 100%), specificity 96.3% (86.3% to 99.3%), positive predictive value 96.2% (85.9% to 99.3%), and negative predictive value 100% (91.5% to 100%). Other similar paper-based groups of measures covering the assessment of 7 areas did not reach such high sensitivity and specificity values (data not shown). Table 5 displays the scores included in this group.
We observed a high frequency (48%) of neurocognitive dysfunction in our sample of HIV-infected adults, which mainly comprised middle-aged men on antiretroviral therapy with a heterogeneous spectrum of clinical conditions. The variables that were significantly associated with this dysfunction were lower nadir CD4 count, being on antiretroviral treatment, fewer years of education, and presence of potential comorbidities for NCI. These findings are consistent with those of previous works reporting an elevated prevalence of neurocognitive dysfunction in people with HIV and mostly identifying the same demographic and clinical risk factors for NCI.1,9
The main objective of our investigation was to find a brief and feasible paper-based method to screen for NCI, principally to facilitate the diagnosis of HAND. We found the highest accuracy for detecting NCI in the combination of 3 measures provided by the tests, TMT-A, TMT-B, and COWAT. We called this combination the NEU Screen. The sensitivity and specificity were 74.5% and 81.8%, respectively. The 3 measures assess attention/working memory, executive functioning, and verbal fluency, which are among the most frequently impaired neurocognitive functions in HIV-infected patients.1,7,9 At all stages of our investigation, our focus was on feasibility in routine practice. Therefore, we sought a practical paper-based tool with a short application time and selected the combination that most accurately indicated the presence of NCI. An additional advantage of our choice was the absence of copyright restrictions in the 3 tests.
Other tools have been proposed as screening methods for NCI in HIV-infected patients. One of the most widely studied is the HIV Dementia Scale,45 which has been adapted from the International HIV Dementia Scale46 to facilitate administration and expand the number of settings where it can be applied. Nevertheless, both scales were designed to screen for dementia, which is considerably less prevalent nowadays thanks to combination antiretroviral therapy. Consequently, some authors have warned about the limitations of using the HIV Dementia Scale or International HIV Dementia Scale to screen for milder forms of NCI, highlighting that their main application should be to screen for dementia or severe forms of impairment.47–50
NCI can also be rapidly detected in the HIV-infected population using the Montreal Cognitive Assessment (MoCA)51 and the Brief NeuroCognitive Screen (BNCS).44 These paper-based tools are easily administered as part of the routine care of HIV-infected patients. However, several characteristics should be borne in mind when applying them in clinical practice. Koski et al52 compared MoCA with computerized tools and found that MoCA was less accurate when used alone; therefore, they recommended using it in combination with other sensitive screening tools (computerized or noncomputerized). In fact, in a recent study published by Overton et al,53 the authors reported 63% sensitivity and 71.2% specificity as the best combination for NCI in 200 HIV-infected patients with a high rate of impairment (64%). When the cutoff score was changed from ≤25 to ≤27, the sensitivity increased to 89.8%, although the specificity fell to 42.5%. The BNCS is comparable with the NEU Screen because it includes the TMT-A, TMT-B, and Digit Symbol test from the WAIS-III. We compared the BNCS with the NEU Screen and found that the specificity in our European sample was slightly higher than that observed with the NEU Screen (85.4% vs 81.8%), although the sensitivity was lower (66.6% vs 74.5%). The main difference between the BNCS and the NEU Screen is that the former emphasizes the measurement of information processing speed, whereas the latter introduces the assessment of verbal fluency. This observation is particularly important in light of recent findings describing how domains, such as verbal fluency and executive functioning, are becoming increasingly affected, in contrast with other typically impaired domains, such as attention/working memory and information processing speed.54 Other tools to screen for NCI in HIV-infected patients have been proposed because of their higher sensitivity than paper-based methods. These include the CogState55 and a pair of scores proposed by Carey et al,43 which have sensitivities of 90% and 78%, respectively. Nonetheless, because our priority was to develop a tool that could be easily applied in clinical practice, we placed emphasis on simplicity and feasibility, thus excluding instrumental tests and tools affected by copyright issues.
Our findings are similar to those of a recent report by Moore et al,56 who analyzed a large number of neurocognitive score combinations to develop a brief battery of tests to screen for NCI in adults with HIV. However, both study designs differ in several relevant aspects. First, the populations studied had markedly different characteristics. The subjects analyzed by Moore et al were early-managed military beneficiaries, whereas ours comprised HIV-infected outpatients attended in 7 Catalan hospitals. There were also differences between time since HIV diagnosis [5 years (IQR, 2–11) vs 10 years (IQR, 3–18), respectively] and prevalence of comorbidities (5% vs 55%). These discrepancies could significantly affect the frequency of NCI detected. In the study by Moore et al, the rate of NCI was substantially lower than in ours (19% vs 48%). Accordingly, we detected a similar rate to that of most published reports, thus allowing us to feel more comfortable using the presence of NCI as the gold standard for comparison. Another crucial difference involved the instrumental requirements. Moore et al compared data according to the number of scores considered and expected time for administration, whereas our primary focus was on paper-based tests, followed by time for administration. As stated above, the basis of our approach was maximum clinical applicability. Therefore, although the objectives of both investigations were similar, it is important to highlight key differences in their designs.
In addition to searching for a rapid screening tool, we performed additional analyses to ascertain the accuracy of longer paper-based combinations used to detect NCI that assess more than 2 or 3 cognitive domains. We identified a combination of 7 scores evaluating 7 domains that were highly accurate for detecting impairment and that presented 100% sensitivity and 96.3% specificity. Given the expected time for application (∼30–35 minutes) and the wider group of neuropsychological tools included, we suggest using this combination as an abbreviated neuropsychological battery, rather than as a specific screening tool. Moreover, the potential advantages of this method highlight its usefulness in settings with limited access to neuropsychological resources or when the time to apply more comprehensive assessment methods is restricted. Furthermore, both the NEU screen and the reduced paper-based battery could facilitate the integration of briefer neuropsychological assessments in longitudinal clinical follow-ups or in prospective clinical trials; however, as our analyses were cross-sectional, we were unable to investigate this hypothesis. As suggested by other investigators, the expected practice effect in the repeated use of neurocognitive assessments should be taken into account,57–59 although few data are available on this undesirable consequence affecting both the proposals we present.
Our study is subject to a series of limitations. Our sample size was similar to that of previous studies, yet it was still small. Sample size is a key characteristic in works investigating screening methods for NCI in HIV infection, given the potential bias arising from heterogeneous demographic features and clinical profiles of HIV-infected patients. Consequently, our study could lack the necessary representativeness of such a sample. Additionally, the number of participants with potential confounding comorbidities was high, and this effect could influence the prevalence of NCI.1,7,9 Although comorbidities were not severe and NCI rates were similar to those of patients without confounding factors, this limitation could negatively affect the accuracy of the gold standard we applied. An additional consideration is the limitation imposed by language. Despite its multicenter design, our study was performed in a small area (Catalonia, Spain) in a Spanish-speaking population; therefore, findings should be restricted to this setting. In addition to the characteristics of the individuals studied, another limitation could concern the scores included in the NEU Screen. Although 3 measures are suggested for the assessment of 3 different areas, verbal memory is not taken into consideration. An advantage of the NEU Screen over other proposed tools is the wider range of neurocognitive domains covered; however, as memory complaints are not covered, sensitivity could be lower.
In summary, we recommend the NEU Screen for rapid and practical detection of NCI in HIV-infected patients. Definitively, data from future studies should consolidate our findings. An appropriate validation study is required, particularly considering the characteristics of our mostly well-educated sample of treated men and the specific use of tests in Spanish. Nonetheless, given its ease of application in routine practice, and the time required for the administration, the NEU Screen could be initially used to detect NCI in different settings where access to resources can be difficult. In our opinion, comprehensive neuropsychological test batteries provide robust data on neurocognitive functioning in the HIV-infected population; however, the NEU Screen could prove particularly valuable in the initial stages of the diagnosis of HAND and in clinical settings where access to neuropsychological resources is limited.
MEMBERS OF THE NEU STUDY GROUP
The members of the NEU Study Group are the authors of this study and the following authors: M. Bernaus (Consorci Sanitari Parc Taulí, Barcelona, Spain), J. Blanch (Hospital Clínic i Provincial de Barcelona, Barcelona, Spain), E. Deig (Fundació Asil, Hospital de Granollers, Barcelona, Spain), Ll. Force (Consorci Sanitari Hospital de Mataró Hospital, Barcelona, Spain), À. Massabeu (Hospital de Palamós, Girona, Spain), A. Raich (Althaia Xarxa Assistencial, Barcelona, Spain), I. Nieto-Verdugo (Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain), J. Toro (Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain), M. González-García (Universitat Autònoma de Barcelona, Bellaterra, Spain), and A. Tuldrà (Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain).
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Keywords:© 2013 by Lippincott Williams & Wilkins
neurocognitive impairment; screening methods; HIV infection