Pietro Balestra

Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors.

Objective:Although highly active antiretroviral therapy (HAART) can reverse HIV-related neurocognitive impairment (NCI), neuropsychologic (NP) deficits may persist in a substantial proportion of patients despite antiretroviral treatment. We assessed the prevalence and predictors of persistent NP deficits despite long-term HAART in patients with HIV-related NCI. Methods:A group of 94 patients with HIV-related NCI underwent 2 to 7 serial NP batteries, neurologic examination, and brain imaging studies. Patients received HAART for a mean of 63 (range: 6-127) months. According to NP assessment results, patients were considered to have reversible or persistent NP deficits. Kaplan-Meier analyses and Cox proportional hazards models were used to analyze time to first evidence of NP deficit reversion. Results:Persistent NP deficits were observed in 59 (62.8%) patients. Age, gender, Centers for Disease Control and Prevention stage, risk category, CD4+ cell count, plasma viral load, and use of central nervous system-penetrating drugs were not associated with persistent NP deficits. By contrast, patients with persistent NP deficits were less educated and showed poorer baseline performances in NP measures exploring concentration and speed of mental processing, memory, and mental flexibility. In multivariable analyses, only the baseline severity of NCI, as measured by the composite NPZ8 global score (odds ratio = 3.07, 95% confidence interval: 1.54 to 6.08; P = 0.001) remained significantly associated with persistent NP deficits. Conclusions:The severity of NCI at HAART initiation seems to be the strongest predictor of persistent NP deficits despite long-term HAART. Our data indicate that HAART should be initiated as soon as NCI is diagnosed to avoid potentially irreversible neurologic damage.

Prevalence and risk factors for human immunodeficiency virus–associated neurocognitive impairment, 1996 to 2002: Results from an urban observational cohort

To assess prevalence and risk factors for human immunodeficiency virus (HIV)-related neurocognitive impairment (NCI), the authors performed a 7-year survey in the period 1996 to 2002. A total of 432 patients were examined. HIV-related NCI was diagnosed in 238 patients (55.1%), meeting the HIV dementia (HIV-D) criteria in 45 (10.4%). The prevalence of both NCI and HIV-D did not change significantly during the study period. Compared with patients without NCI, patients with NCI were older (40.4 versus 38.2 years; P = .003), had a higher prevalence of positive HCV serology (61.1% versus 38.9%; P = .003), and a lower nadir CD4 cell count (156 versus 222 cells/μl; P < .001). Compared with patients seen during 1996 to 1999, patients with NCI seen during 2000 to 2002 were older (40.7 versus 38.8 years; P = .004), had a less advanced disease stage (previous acquired immunodeficiency syndrome [AIDS] 28.8% versus 65.7%; P < .001) and a higher nadir CD4 count (174 versus 132 cells/μl; P = .026). This study showed an unchanged prevalence of both HIV-related NCI and HIV-D in the period 1996 to 2002. The authors found evidences for new additional potential risk factors for HIV-related NCI (older age, lower nadir CD4 count, positive hepatitis C virus [HCV] serology), and for a change of risk factors for NCI in the late highly active antiretroviral therapy (HAART) era (older age, less advanced disease, higher nadir CD4 count).

Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders.

Objective:Although HIV-associated neurocognitive disorders should be treated with highly active antiretroviral treatment (HAART) regimens with good central nervous system (CNS) penetration, the definition of neuroactive HAART remains controversial. We compared 2 ranking systems to measure HAART neuroeffectiveness. Methods:Patients with (n = 93) or at risk for (n = 92) HIV-associated neurocognitive disorders underwent neuropsychological (NP) test batteries before HAART initiation and at follow-up. Changes in normatively adjusted summary NP test z scores were calculated for each subject. Two neuropenetration scores were calculated: the central nervous system penetration reference score (number of drugs in the combination among zidovudine, abacavir, stavudine, lamivudine, efavirenz, nevirapine, indinavir, and lopinavir-ritonavir) and the CNS penetration-effectiveness (CPE) score: a summary score of 1 (high: zidovudine, abacavir, nevirapine, amprenavir-ritonavir, atazanavir-ritonavir, indinavir-ritonavir, and lopinavir-ritonavir), 0.5 (intermediate: stavudine, lamivudine, emtricitabine, efavirenz, amprenavir, atazanavir-ritonavir, and indinavir), and 0 (low penetration: remaining antiretrovirals) for each drug in the combination. Main outcome measures were changes in global NPZ scores and in summary z scores on 5 domains. Results:At regression analyses, higher CPE scores correlated with greater improvements in NPZ-4 (P = 0.0283), NPZ-8 (P = 0.0071), concentration and speed of mental processing (P = 0.0046), and mental flexibility (P = 0.0262) summary z scores. The correlation was stronger among NP-impaired patients. By contrast, higher estimates of neuroeffectiveness with the alternative system showed no correlation. No association was seen between CD4 and plasma viral load changes with both scores. Conclusions:The CPE score represents a step forward toward the identification of a clinically useful approach to estimating HAART ability to improve cognition.

Neurocognitive performance and quality of life in patients with HIV infection.

We examined the relationship of HIV-related cognitive impairment and health-related quality of life (QoL). Subjects were administered measures of cognitive function (a battery of 17 neuropsychological tests) and of QoL (the MOS-HIV questionnaire). Study measures also included comprehensive clinical and neurological evaluation, laboratory testing, and brain imaging studies in patients with impaired neuropsychological evaluation. One-hundred and eleven subjects were examined. Cognitively impaired patients (33.3%) reported poorer QoL scores in all domains (p < 0.05): physical health summary score (PHS) (44.6 vs. 49.9), mental health summary score (MHS) (37.7 vs. 44.4), pain (67.6 vs. 79.4), physical functioning (75.9 vs. 87.7), role functioning (32.4 vs. 41.5), social functioning (70.3 vs. 83.5), mental health (48.2 vs. 61.0), energy (53.1 vs. 63.0), health distress (60.8 vs. 75.5), cognitive functioning (CF) (60.5 vs. 71.8), general health perceptions (29.2 vs. 43.4), and QoL (36.5 vs. 47.0). The number of altered neuropsychological tests correlated significantly with MHS (p < 0.001), PHS (p < 0.03), CF (p < 0.02), and QoL (p < 0.02) scores. A correlation between seven of seven neuropsychological measures exploring speed of mental processing, three of four exploring mental flexibility, four of six exploring memory, and two of two exploring fine motor functioning and MHS, PHS, CF, or QoL scores was also found. Poor performance on the Digit Symbol test was most strongly associated with poor MHS (OR 1.04, 95% CI 1.01-1.08, p < 0.009) and PHS (OR 1.04, 95% CI 1.01-1.08, p < 0.01) scores, controlling for CD4 count, previous AIDS diagnosis, receiving HAART, and drug abuse. Cognitive impairment is associated with poor QoL. People with more severe cognitive impairment have the highest probability of having a poor QoL. Cognitive impairment in any cognitive domain explored in our battery is also associated with poor QoL. Poor performance on the Digit Symbol Test is the strongest predictor of poor QoL.

Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex

ObjectiveZidovudine (ZDV) is an inhibitor of HIV replication that may have a beneficial effect on patients with AIDS dementia complex (ADC). However, little is known about the association between long-term ZDV treatment and severity of ADC, ZDV dose or clinical and laboratory response to therapy. DesignAn open study on ZDV administration in 30 consecutive patients with ADC. SettingAn infectious diseases hospital. PatientsThirty consecutive patients followed-up for 12 months. InterventionsThree oral ZDV doses were used: 1000 mg (nine patients), 750 mg (eight patients) and 500 mg (13 patients) per day, depending on haematological status. Main outcome measuresClinical and neurological examinations, neuropsychological evaluations, high-field brain magnetic resonance imaging (MRI) and 99mtTc-HM-PAO single photon emission computerized tomography (SPECT). ResultsA favourable clinical response, defined as reversal to a less severe ADC stage (Price and Brews criteria), was observed after 1, 3, 6, 9 and 12 months in 15, 22, 25, 19 and 14 patients, respectively. Neither severity of ADC at entry nor ZDV dose correlated with response to treatment. Seven patients died during the 12-month follow-up. The only factor associated with longer survival was ADC severity at entry (12-month survival, 0.94 and 0.53, in patients in stages 1 or 2 and in stages 3 or 4, respectively; P< 0.01). After 6–12 months of ZDV treatment six patients who initially responded to therapy showed a relapse in initial ADC stage, and two patients a less severe neurological deterioration. Neuropsychological evaluations showed significant improvement in the Wisconsin Card-Sorting test (P = 0.006 for categories, P = 0.029 for perseverative errors), which is particularly sensitive to cognitive and frontal-lobe type functions. Brain MRI revealed a reduction of the extent of white matter lesions in six out of 13 patients, who also showed clinical improvement. SPECT scanning revealed a reduction in the extent of uptake defects concomitant with clinical response in nine out of 14 patients. ConclusionsZDV is effective in most patients with mild to end-stage ADC, although the benefit is sometimes only transient; several relapses and deaths occurred after the sixth month of treatment.

Changes in neurocognitive performance in a cohort of patients treated with HAART for 3 years

Objectives: To describe changes in HIV‐associated neurocognitive impairment in patients treated with highly active antiretroviral therapy (HAART) for at least 3 years. Methods: Prospective, observational study of comprehensive neuropsychologic (NP) testing, neurologic examination, and laboratory measures before HAART and after 6, 15 and 45 months of HAART, on 28 consecutive patients seen in our department since April 1996. Results: At baseline, 16 patients were neurocognitively impaired and 12 were not. Among the 16 impaired patients, 5 patients failed to meet the criteria for impairment after 6 months and 9 patients after both 15 and 45 months of HAART, respectively. Statistically significant improvements (p ≤ .01) were seen in two of six measures exploring the concentration and speed of mental processing, two of three measures exploring mental flexibility, in one of five measures exploring memory, and in two of two measures exploring fine motor functions. Unimpaired study subjects performed better than impaired ones in 10 of 17 measures at baseline, in eight of 17 after 6 months, in six of 17 after 15 months, and in seven of 17 after 45 months of HAART. Conclusions: During the course of HAART, patients experienced a positive and sustained improvement in their neurocognitive performance. However, the presence of 7 of 16 (43.7%) patients with neurocognitive impairment, and the persistence of statistically significant differences in the neurocognitive performance between impaired and unimpaired patients after more than 3 years of HAART, suggests that ongoing HIV‐related neurologic damage can occur even during potent antiretroviral treatment.

Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART.

The objective of the study was to determine the association of neurocognitive impairment with health-related quality of life (HRQoL) in patients receiving highly active antiretroviral therapy (HAART). Seventy subjects were cross-sectionally analysed with a standardized neuropsychological test battery and a questionnaire including an Italian translation of the MOS-HIV Health Survey. The presence of neurocognitive impairment was significantly associated with lower HRQoL scores: pain (P = 0.03), physical functioning (P = 0.01), role functioning (P = 0.01), social functioning (P = 0.029), mental health (P = 0.001), energy (P = 0.036), health distress (P = 0.002), cognitive functioning (P = 0.05), current health perception (P <0.001), physical health summary score (PHS) (P = 0.005), mental health summary score (MHS) (P = 0.002). Years of education (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.65-0.96), PHS (OR 0.71; 95% CI 0.54-0.95) and MHS (OR 0.67; 95% CI 0.51-0.88) were also associated with cognitive impairment. Neurocognitive impairment in patients receiving HAART was associated with reduced HRQoL. Identifying cognitive impairment may provide motivation for additional treatment to help patients to compensate for deficits in functioning.

Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy

Objective: To analyze the effect of antiretroviral therapy, including drugs that have good penetration in cerebrospinal fluid (CSF), on neuropsychologic performance. Methods: One hundred sixty-five HIV-1-infected patients exposed to a stable highly active antiretroviral therapy (HAART) regimen were studied. Neuropsychologic examinations were performed for all patients. Results: A total of 50.3% of patients were impaired. In multivariate analysis, older age (for 10-year increase, odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.2 to 10.4; P< 0.0001) and higher plasma HIV-1 RNA levels (OR = 1.90, 95% CI: 1.1 to 3.2; P = 0.021) at testing were independently associated with an increased probability of impaired neurocognitive performance, whereas higher educational level was a protective factor (OR = 0.76, 95% CI: 0.65 to 0.90; P=0.001). A significant linear correlation was observed between the neuropsychologic z score for 8 tests (NPZ8) score, a quantitative parameter of neurocognitive impairment, and CD4 cell count at neuropsychologic testing (R = 0.273, P = 0.001) and between the NPZ8 score and the patients age (R = 0.288, P = 0.001). Conclusions: Our study indicates that the use of stable HAART, including multiple drugs that have good CSF penetration, was not associated with neuropsychologic performance. To prevent independent replication of HIV in CSF with better control of a relevant reservoir of HIV is one of the crucial aims of therapeutic strategy.

Acute disseminated encephalomyelitis as manifestation of primary HIV infection.

The authors report a 27-year-old woman with clinical, MRI, virologic, and CSF findings consistent with acute disseminated encephalomyelitis as a manifestation of primary HIV infection. Improvements in the clinical and MRI findings and a reduction in HIV RNA levels, both in plasma and in the CSF, were observed during highly active antiretroviral therapy.

Zika Virus Infection in the Central Nervous System and Female Genital Tract

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