HIV can cause a wide range of neurocognitive complications now regrouped under the acronym of HANDs, for HIV-associated neurocognitive disorders . These complications, mainly due to neuropathological changes within the basal ganglia and the white matter, typically lead to mental slowing, memory loss, difficulties in complex tasks requiring executive functions, as well as motor disorders . In addition, affected individuals can present with behavioral abnormalities, such as apathy, and a decrease in spontaneity or emotional responses. In fact, the new nosology for HANDs recognizes three conditions given hereafter by order of increasing severity: HIV-associated asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorders (MNDs), and HIV-associated dementia (HIV-D).
After HAART have become available, the profile of HANDs has changed. First, although the incidence of HIV-D has significantly decreased , its prevalence has increased , as HIV-positive patients live much longer than before the HAART era . Similarly, the prevalence of minor cognitive deficits seems to have increased, with reported prevalence between 20 and 50% of HIV-positive patients [3,4,6–8]. This wide range may reflect the heterogeneity of clinical groups. Indeed, in the studies [7,9,10] performed in the HAART era, only half of the patients had an undetectable viremia at the time of the neuropsychological examination. Therefore, whether there is really a high prevalence of HANDs in optimally treated HIV-positive patients, that is, those with long-standing aviremia is not entirely resolved. It is also difficult to know when to be concerned for a patient who complains of memory loss, difficulties in concentration, and the like. Population-based studies conducted in HIV-negative healthy individuals have shown that the complaint of memory loss is frequent (20–70% according to studies)  but only rarely associated with current objective cognitive impairment [12,13]. The positive predictive value of cognitive complaints for the presence of HANDs in HIV-positive patients is unclear. Furthermore, there is no validated easy-to-perform test to screen for minor cognitive disorders in HIV-positive patients. In the pre-HAART era, the HIV-dementia scale (HDS) was developed to identify HIV-D and demonstrated a sensitivity of 80% when the score was 10 or less for a maximum of 16 points . However, the accuracy of the HDS to detect minor cognitive deficits in the HAART era remains unknown and was recently questioned [15,16]. Yet, a simple way to identify HIV-positive patients with minor cognitive disorders would be useful, as these troubles are associated with a decrease in the quality of life, diminished compliance with HAART, and increased mortality .
In this study, we determined how frequently HANDs could be detected in patients who are optimally treated with HAART, as reflected by a long-standing period of undetectable viremia. In this homogeneous population, we also characterized HANDs and examined its functional repercussion by correlating it with subjective complaints. Finally, on the basis of our data, we reassessed the value of the HDS to detect minor cognitive disorders in HIV-positive patients with undetectable viremia.
Selection of study participants
This study was advertised in the outpatients HIV clinics of both Lausanne and Geneva University hospitals, as well as in private practice of physicians who take care of HIV-positive patients in the Lake Geneva region. Inclusion criterion was undetectable HIV-1 RNA concentrations (<50 copies/ml) for more than 3 months before study entry. Exclusion criteria were: major opportunistic infection of the brain in the past 3 years, any other opportunistic infection not affecting the brain in the past 12 months, active drug use, major depression according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria, and pregnancy. The prevalence of cognitive complaints in the general aviremic HIV-positive population was estimated in 200 patients. A short questionnaire was distributed to the physicians taking care of HIV-positive patients in the Lake Geneva region. This questionnaire included three questions: ‘Do you experience frequent memory loss (e.g. do you forget the occurrence of special events even the more recent ones, appointments, etc.)’? ‘Do you feel that you are slower when reasoning, planning activities, or solving problems’? ‘Do you have difficulties paying attention (e.g. to a conversation, a book, or a movie)’? For each question, patients could answer ‘never’, ‘hardly ever’, or ‘yes, definitely’. Complaining patients were considered to be those answering ‘yes, definitely’ on at least one question. Among the 200 questioned patients, 50 patients without cognitive complaints agreed to undergo detailed neuropsychological testing. These patients were compared with 50 complaining patients who had previously been identified and tested.
For each patient, we determined the central nervous system (CNS) penetration-effectiveness (CPE) rank of HAART . Individual drugs were assigned a score based on the level of CNS penetration (0 = low, 0.5 = intermediated, and 1 = high), and the CPE rank was calculated by adding up the scores of each antiretroviral drug in the regimen. Treatments other than HAART, including antidepressants prescribed for minor depressive signs and methadone, as well as coinfection with hepatitis C virus (HCV), were recorded but were not exclusion criteria.
Both subcortical and cortical functions were evaluated. Subcortical functioning was assessed using the Reaction time, Rapid Visual Information Processing, and Spatial Working Memory from the Cambridge Neuropsychological Test Automated Battery , the Trail Making Test (TMT) parts A and B , and the digit spans backward and forward . Cortical functioning was assessed through the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). This scale is a reliable and valid instrument originally used to assess cognitive dysfunction in individuals with Alzheimer's disease. It is composed of 11 cognitive tasks assessing orientation, verbal memory, language skills, and praxis . For all these tests a deficit score was calculated using Z-scores retrieved from available normative data. Finally, the HDS and the National Adult Reading Test (NART)  were performed in all patients.
According to the updated research nosology for HANDs , patients were then diagnosed as having: ANI [cognitive deficits involving at least two domains (e.g. language, praxis, memory, attention, executive functions, or processing speed) and documented by performances of at least one Z-score below the mean, without interference in everyday functioning], MNDs (cognitive deficits involving at least two domains and documented by performances of at least one Z-score below the mean, mild interference in everyday functioning), HIV-D (cognitive deficits involving at least two domains and documented by performances of at least two Z-score below the mean, marked interference in everyday functioning), or no cognitive impairment.
Behavioral and health status examination
Mood disorders were measured for all patients using the Hospital Anxiety and Depression scale addressing depressive (HAD-D) and anxious (HAD-A) symptoms, separately. Patients were considered depressed or anxious if the HAD-D or HAD-A subscale score was at least 10 of 21 . Behavioral changes were assessed with a patient's relative using the neuropsychiatric inventory (NPI) . In this scale, the maximum NPI total score is 144 and the maximum score is 12 for each of the 12 symptoms assessed. Finally, quality of life (QoL) was assessed with the Medical Outcome Study HIV Health Survey (MOS HIV)  in which scores range from zero (worst) to 100 (best).
Statistical analyses were conducted using a STATA software package (version 10.0; StataCorp LP, College Station, Texas, USA). A disease duration–age index (disease duration/age) was built to measure the combined effect of these two variables on cognition . In the same way, a HAART–disease duration index was computed (HAART duration/disease duration). Differences on demographic factors (age, sex, and NART score), course of HIV infection (time since diagnosis, duration of aviremia, nadir and current CD4+ T cells count, platelets count, CPE rank for HAART, duration of current HAART, and HAART–disease duration index), medication, mood or behavioral disorders, and impact on QoL were examined using χ2 tests and Fisher exact tests for the comparison of categorical variables, and Mann–Whitney rank-sum tests for the comparison of continuous variables. Significance was set at a P value of less than 0.05 for all statistics. Because the analyses involved 39 measures, we also applied a Bonferroni corrected standard P level of P less than 0.001 for multiple comparisons. Finally, a receiver operating characteristic (ROC) curve was calculated by means of a nonparametric approach to define the best cutoff score for the HDS to detect HANDs.
Prevalence of cognitive complaints in the general aviremic HIV-positive population
On the basis of our questionnaire, the prevalence of cognitive complaints in the general aviremic HIV-positive population was 27% (54/200): 18% pertained to memory difficulties, 16% to mental slowing, and 9% to attention deficits.
Description of the study cohort undergoing neuropsychological examination
Fifty noncomplaining HIV-positive patients, identified among the 200 patients who answered the questionnaire, and 50 additional HIV-positive patients with cognitive complaints, who had been previously identified, underwent neuropsychological testing. The HIV clinical characteristics of both groups are presented in Table 1. In the whole cohort, study patients were predominantly white (73%) and men (72%), with a median age of 46 (range 30.3–69.6) years. Seventy-three percent had at least a high school education. Eighty percent had been aviremic for more than 2 years prior to inclusion in the study. All patients were on HAART, except one elite controller who had been aviremic for 9 years. Forty-seven patients (47%) had a CPE rank of at least 2. Nineteen patients (19%) had HCV coinfection with a median viral load of 92 000 IU/ml (range 0–1.2 × 107). Six patients (6%) had presented a cerebral toxoplasmosis an average 5.8 ± 2.4 years prior the inclusion in the study. All six had recovered well but mild cognitive deficits still persisted in four of them. Eleven patients were taking antidepressants and eight had a past history of drug use (mainly heroin) and were currently taking methadone.
Prevalence of HIV-associated neurocognitive disorders in aviremic HIV-positive patients
Forty-two patients (42%) were diagnosed with ANI, 28 (28%) with MNDs, four (4%) with HIV-D, whereas 26 (26%) were cognitively preserved. Overall, the proportion of the patients experiencing HANDs was 74% (Fig. 1).
Objective evidence of HANDs was more frequent in complaining than in noncomplaining patients (84 vs. 64%, respectively, P < 0.001). In the complainers group, 12 patients (24%) were diagnosed with ANI, 26 (52%) with MNDs, four (8%) with HIV-D, whereas eight (16%) were cognitively preserved. In comparison, 30 of 50 noncomplaining patients were diagnosed with ANI (60%), only two experienced MNDs (4%), and the remainder of the group had a normal neuropsychological examination (18/50, 36%, Fig. 1).
Taking into account the observed prevalence of subjective complaints (27%) as well as our neuropsychological findings, we computed an estimated prevalence of HANDs in the general aviremic HIV-positive population with a long-term suppression of viremia. This prevalence was estimated to be 69% (Fig. 1). Of these patients with HANDs, 50% would suffer from ANI, 17% from MNDs, and 2% from HIV-D.
Comparison of HIV-positive patients with and without cognitive complaints
As compared with noncomplaining patients, complainers had a higher disease duration–age index (P = 0.04), a shorter duration of aviremia (P = 0.0003), and HAART–disease duration index (P = 0.006), showed more depressive (P = 0.001) and anxious signs (P = 0.001), and were more likely to be taking methadone (P = 0.003) or antidepressants (P = 0.03). However, after Bonferroni correction, only duration of aviremia remained associated with cognitive complaint, whereas mood symptoms showed a strong trend (Table 1).
Comparison of HIV-positive patients with and without HIV-associated neurocognitive disorders
As compared with those without HANDs (n = 36), patients with HANDs (n = 74) were more likely to be women (P = 0.007), to have lower NART scores (P = 0.004) and to present neuropsychiatric symptoms in the NPI (P = 0.01). However, after correction for multiple comparisons, these differences were no longer statistically significant (Table 1). Patients with HANDs were more likely to have lower mean HDS scores (10.1 ± 3.8 vs. 14.4 ± 2.3, P < 0.0001). These patients had obviously lower mean Z-scores in all the cortical and subcortical tests (P < 0.0001, Fig. 2) and the TMT was the one they most frequently failed. Finally, HANDs were associated with decreased scores in two health status domains of the MOS HIV. These were physical function (66.9 ± 30.1 vs. 86.2 ± 22.7, P = 0.0006) and social function (73.7 ± 26.2 vs. 94.6 ± 10.7, P = 0.0002).
Comparison of HIV-positive patients with and without HIV-associated neurocognitive disorders-related functional impairment
By definition, the ANI category encompasses patients with asymptomatic HANDs, thus without functional repercussion. We split the cohort between patients with functional impairment (MNDs and HIV-D) and without functional impairment (ANI and normal examination). As compared with patients experiencing no functional impairment (n = 68), those with functional decline (n = 32) were more likely to have a longer duration of HIV infection (P = 0.05), a higher disease duration–age index (P = 0.02), and a lower HAART–disease duration index (P = 0.01). In addition, they were more frequently taking methadone (P = 0.007) or antidepressants (P = 0.002) and showed more depressive (P < 0.001) or anxious (P < 0.001) signs (Table 1). After correction for multiple comparisons, clinical factors no longer accounted for HANDs.
HANDs producing interference in daily living (MNDs and HIV-D) were associated with decreased scores in eight health status domains of the MOS HIV. Those were perceived health (34.5 ± 19.7 vs. 61 ± 25.8, P < 0.0001), role function (38.7 ± 44.2 vs. 77.9 ± 37, P < 0.0001), social function (59.4 ± 21 vs. 88.2 ± 21.1, P < 0.0001), cognitive function (56 ± 23.6 vs. 81.2 ± 17, P < 0.0001), mental health (51.9 ± 19.2 vs. 72.9 ± 16.1, P < 0.0001), energy/fatigue (46.1 ± 21.6 vs. 68.2 ± 17.9, P < 0.0001), health distress (52.3 ± 27.6 vs. 80.7 ± 24, P < 0.0001), and global QoL (56.5 ± 19.3 vs. 74.6 ± 20.5, P = 0.0001).
HIV dementia scale sensitivity and specificity to HIV-associated neurocognitive disorders
On the basis of the cutoff of 10 points or less classically used for the detection of HIV-D, we found that, as compared with the above-mentioned neuropsychological battery, the HDS yielded a test sensitivity and specificity of 54.1 and 96.2% to detect HANDs.
Using a ROC curve, we determined that the best cutoff score on the HDS for the recognition of patients with HANDs was a score of 14 points or less (P < 0.001) (Fig. 3). This cutoff yielded a sensitivity of 83%, a specificity of 63%, and a positive predictive value of 92% to detect HANDs in complaining patients. The respective values for noncomplainers were 88, 67, and 82%.
We found that 27% of HIV-positive patients with long-standing undetectable HIV-1 RNA concentration complained of neurocognitive disorders and 84% of them actually presented HANDs. Even in patients with no specific complaints, this percentage was 64%. We could thus infer that the prevalence of HANDs in the general aviremic HIV-positive population was 69% (Fig. 1). This number is somewhat higher than the prevalence of HANDs in patients described in previous reports [3,4,6–8], but most of the studies [3,4,6,8] examining the prevalence of neurocognitive disorders in the HIV-positive population were performed before the revised nosology for HANDs was published, and thus ANI was possibly not accounted for.
The message of our study is that the prevalence of HANDs remains elevated even in HIV-positive patients who are aviremic for a long time. A possible explanation for the development of HANDs is that low-level viral replication, as it occurs with all but the most successful HAART regimens, leads to slow progressive neurodegeneration . However, our results must certainly not be interpreted as a nonefficacy of HAART. Indeed, we found that noncomplainers had a significantly longer duration of aviremia than complainers. Our results do not support a toxicity of HAART either , as patients with a longer duration of HAART treatment tended to have better cognitive performances. These results are supported by a recent longitudinal study  on 48 weeks that showed that the decrease of HANDs was proportional to the duration of HAART. Thus, our data suggest that HAART alleviates HANDs, but raise the question whether HAART is sufficient to make HANDs disappear. Recent studies [17,29,30] have shown that antiretroviral drugs with the highest CPE were the most efficient in suppressing HIV replication in the cerebrospinal fluid. However, the value of CPE for cognitive disorders is more controversial, some having found that a high CPE was associated with better cognitive outcome , others not . We did not observe significant differences of CPE between the different categories of patients (Table 1), although there was a trend for less functional impairment in patients with a CPE of at least 2.
To ensure that there was no other obvious cause than HIV itself to explain HANDs, we tried to minimize confounding factors by not enrolling patients with major depression, active drug addiction, or opportunistic infection of the CNS. Some patients using methadone (8%) or having a remote history of cerebral toxoplasmosis (6%) were enrolled, but none of these factors was found to be associated with HANDs after correction for multiple comparisons. Patients with HCV coinfection (19%) were also accepted and were not found to have a higher prevalence of HANDs as compared with HCV-negative patients. This result is in accordance with a previous study , which showed that cognitive performances in HAART-treated HIV-positive patients with or without HCV coinfection were comparable, whereas, in HAART-naive patients, those with HCV infection did worse than HCV-negative ones. The authors hypothesize that HAART might alleviate the consequence of HCV on cognition and reduce confounding effects. After correction for multiple comparisons, mood symptoms were to some extent related to MNDs or HIV-D. The question arises whether some patients were falsely diagnosed with MNDs or HIV-D while their cognitive disorders were in fact due to depression. Speaking against this hypothesis, authors have reported that HANDs and depression should be considered as two independent processes in HIV-infected patients . Moreover, contrary to major depression, minor depression is associated with only minimal cognitive deficits .
Cognitive complaint was relatively predictive of the presence of HANDs (84% of patients) but not complaining certainly did not rule it out (64% of patients). However, whereas most complainers presented with MNDs or HIV-D, the vast majority of noncomplainers presenting with HANDs had ANI. Thus, in HIV-positive patients, contrary to HIV-negative patients [12,13], cognitive complaints are predictive of actual impairment. Interestingly, a sensitivity analysis of the HDS revealed that a cutoff of 14 points or less was associated with a good sensitivity and a good predictive value to detect HANDs despite a somewhat decreased specificity, either in complainers or noncomplainers. Others have reported that the HDS was not useful to diagnose minor cognitive disorders [15,16]. However, they relied on the classical cutoff of 10 points or less, which clearly decreases the sensitivity of detection of mild forms of cognitive disorders. Whereas the HDS alone is not sufficient to ascertain HANDs, we propose that HIV-positive patients with undetectable viremia and a HDS score of 14 points or less should benefit from a thorough neuropsychological evaluation.
Finally, such as displayed in the Table 1, we did not find clinical and biological differences between patients with and without HANDs. In particular, factors classically associated with cognitive impairment in the pre-HAART era such as viral load, current count or nadir of CD4+ T cells did not appear as important markers, supporting the notion that the spectrum of HANDs has changed [26,34]. Indeed, a change in the pattern of cognitive disorders, characterized by cortical dysfunction in addition to the subcortical ones, has been observed [8,34]. Links between HIV encephalopathy and Alzheimer's disease have even been suggested . Somewhat supporting this hypothesis, we found that, in addition to classical subcortical cognitive deficits, our patients with HANDs exhibited deficits in tests assessing cortical functions (ADAS-cog).
Altogether, our results show that cognitive dysfunction is frequent in virologically optimally treated HIV-positive patients. These data point out the importance of an early diagnosis of HANDs and of a regular follow-up of HIV-positive patients, especially when they complain of cognitive disorders. In addition, our data are in line with other reports suggesting that the spectrum of HANDs may have changed in the HAART era.
This work was supported by a grant from the Swiss HIV Cohort Study (no. 514) to R.A.D.P. and B.H. and by the SNF PP003-106716 to R.A.D.P.
S.S. enrolled and tested participants, analyzed data, and drafted and critically reviewed the manuscript. M.C., V.S., A.C., and J.-P.C. enrolled participants and critically reviewed the manuscript. J.-M.A., E.G., and B.H. designed the study and critically reviewed the manuscript. A.R.A. and I.B. enrolled and tested participants, and critically reviewed the manuscript. R.A.DuP. designed the study, drafted and critically reviewed the manuscript.
There are no conflicts of interests.
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