This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals ...in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 ...years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.
We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML).
We recorded the clinical ...outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood.
Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio HR for death = 0.47, 95% confidence interval CI 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival.
The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.
Pregabalin is effective in several neuropathic pain syndromes. This trial evaluated its efficacy, safety, and tolerability for treatment of painful HIV-associated neuropathy.
This randomized, ...double-blind, placebo-controlled, parallel-group trial included a 2-week double-blind dose-adjustment (150-600 mg/day BID) phase, a 12-week double-blind maintenance phase, and an optional 3-month open label extension phase. The primary efficacy measure was the mean Numeric Pain Rating Scale (NPRS) score, an 11-point numeric rating scale. Secondary measures included Patient Global Impression of Change (PGIC) and sleep measurements.
Baseline mean NPRS score was 6.93 for patients randomized to pregabalin (n = 151) and 6.72 for those to placebo (n = 151). Pregabalin average daily dosage (SD) was 385.7 (160.3) mg/d. At endpoint, pregabalin and placebo showed substantial reductions in mean NPRS score from baseline: -2.88 vs -2.63, p = 0.3941. Pregabalin had greater improvements in NPRS score relative to placebo at weeks 1 (-1.14 vs -0.69, p = 0.0131) and 2 (-1.92 vs -1.43, p = 0.0393), and at weeks 7 (-3.22 vs -2.53 p = 0.0307) and 8 (-3.33 vs -2.53, p = 0.0156). At all other time points, differences between groups were not significant. Sleep measurements and 7-item PGIC did not differ among treatment groups; however, collapsed PGIC scores showed 82.8% of pregabalin and 66.7% of placebo patients rated themselves in 1 of the 3 "improved" categories (p = 0.0077). Somnolence and dizziness were the most common adverse events with pregabalin.
Pregabalin was well-tolerated, but not superior to placebo in the treatment of painful HIV neuropathy. Factors predicting analgesic response in HIV neuropathy warrant additional research.
This Class II trial showed that pregabalin is not more effective than placebo in treatment of painful HIV neuropathy.
To study the outcome of patients with multiple sclerosis (MS) and with natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS).
...MedWatch reports from Biogen-Idec (manufacturer of natalizumab, Tysabri(®)) were reviewed which comprised all 42 cases of natalizumab-related PML cases since its reintroduction until March 2010.
All except 2 patients with natalizumab-related PML were managed by discontinuation of natalizumab and plasmapheresis/immunoadsorption (PLEX/IA). Seventeen patients had contrast enhancement of PML lesions on neuroimaging at the time of diagnosis before withdrawal/removal of natalizumab (early-PML-IRIS) and 23 patients developed contrast enhancement only after withdrawal/removal of natalizumab (late-PML-IRIS). All patients developed IRIS. IRIS was defined as worsening of neurologic deficits during the immune reconstitution following discontinuation of natalizumab, corroborated by inflammatory changes on neuroimaging. Following PLEX/IA, JC viral load in CSF increased by >10 fold in those with early-PML-IRIS but <2 fold in late-PML-IRIS. IRIS developed earlier and was more severe in early-PML-IRIS (p < 0.05). At the last follow-up, all patients had worse EDSS scores but this was higher in patients with early-PML-IRIS compared to those with late-PML-IRIS (p > 0.05). Mortality was comparable between the 2 groups, 29.4 ± 11% vs 21.7 ± 8.8%. Corticosteroid therapy during IRIS was associated with better Expanded Disability Status Scale outcome, p < 0.05.
Early immunologic rebound in natalizumab-associated PML has worse survival and neurologic outcome. PLEX/IA may accelerate IRIS and its impact on the final outcome is unclear. Corticosteroid therapy provides a modest benefit and needs to be systemically studied in a controlled manner in the management of natalizumab-associated PML-IRIS.
Because HIV-related neurocognitive impairment is usually mild and variable, clinical ratings (CR) and global deficit scores (GDS) are recommended for detecting HIV-associated neurocognitive disorders ...(HAND). The CR approach requires impairment in at least two ability domains while the GDS considers number and severity of impairments across all measures. We examined classification agreement and clinical correlates of the two methods. Neurocognitive functioning of 1574 HIV-infected participants was assessed via a comprehensive, seven-domain neuropsychological battery. Global neurocognitive impairment was defined for each participant independently by CR and GDS. Participants were classified into four categories (Dually-normal, impaired by CR-only, impaired by GDS-only, or Dually-impaired). There was 83% concordance between CR and GDS classifications; in total, 56% of participants were deemed impaired by CR and 41% were classified as impaired by GDS. Impairment by GDS virtually guaranteed CR impairment, but 16% of participants were additionally classified as impaired only by CR. As compared to Dually-normal participants, those classified as Dually and CR-only impaired were more likely to have AIDS, have more severe co-occurring conditions, have more severe depressive symptoms, be unemployed, and have more everyday functioning complaints (ps < .05). Impairment classifications of the two methods were in high agreement; however, more people were classified as impaired using the CR approach compared to the GDS approach. Those impaired according to CR-only showed fewer neurocognitive and functional deficits than the Dually-impaired participants, but more of these deficits than Dually-normal participants. The CR approach may be most appropriate for detecting more subtle forms of neurocognitive impairment. Clinicians and researchers should recognize the strengths and weaknesses of each method when evaluating neurocognitive complications in HIV.
Toxoplasma gondii is an important food- and waterborne opportunistic pathogen that causes severe disease in immunocompromised patients. T. gondii has an unusual clonal population structure consisting ...of three widespread lineages known as I, II, and III. To establish the genotypes of strains of T. gondii associated with human toxoplasmosis, we have developed a set of four highly sensitive and polymorphic nested PCR markers. Multiplex nested PCR analysis was used to genotype parasites in cerebral spinal fluid samples from 8 of 10 human immunodeficiency virus-positive patients. Remarkably, a majority of these patients had infections with type I strains or strains containing type I alleles, despite the fact that this lineage is normally uncommon in humans and animals. Multiplex analysis of these four unlinked makers was able to distinguish all three common genotypes and also detected two strains with mixed genotypes. Further analysis based on sequencing of a polymorphic intron revealed that one of these recombinant strains was an exotic lineage distinct from the archetypal clonal lineages. The multiplex nested PCR analysis described here will be useful for analyzing the contribution of parasite genotype to toxoplasmosis.
HIV-associated neurologic disorders (HAND) continue to develop in many patients with HIV. CSF amyloid measurements in HAND have been reported to be similar to those in dementia of the Alzheimer type ...(DAT). Confirmatory evaluation of this finding in carefully evaluated subjects is needed.
CSF specimens were obtained from subjects clinically categorized with normal cognition from the general population, HIV+ subjects with normal cognition, HIV+ subjects with impaired cognition, or presumed HIV- subjects with mild DAT. CSF measurements of beta-amyloid((1-42)) (Abeta42), beta-amyloid((1-40)) (Abeta40), total tau (t-tau), and phosphorylated tau (p-tau181) were performed.
CSF Abeta42 measured in 49 HAND subjects had a median level of 501 pg/mL, which was lower than that of 50 controls of similar age who had median of 686 pg/mL (p < 0.0001) or 21 HIV+ subjects without cognitive impairment who had median of 716 pg/mL (p < 0.003). HAND subjects had similar CSF Abeta42 to 68 subjects with mild DAT. There was no difference of CSF Abeta40 between the groups. Tau and p-tau181 was elevated in DAT, but slightly lower than control in both HIV+ groups.
beta-Amyloid((1-42)) (Abeta42) measurements in CSF of cognitively impaired patients with HIV are similar to those in patients with mild dementia of the Alzheimer type (DAT). Normal or slightly depressed CSF tau and p-tau181 measurements distinguish these patients with HIV-associated neurologic disorders (HAND) from patients with DAT. Further evaluation of amyloid metabolism in patients with HIV cognitive disorder is needed to understand the implications of depressed CSF Abeta42 in the setting of HAND.
Dysregulated iron transport and a compromised blood–brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport ...and/or angiogenesis—ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)—as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment odds ratio (OR) 2.17,
p
= 0.006 and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (
p
= 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (
p
= 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both
p
= 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both
p
< 0.05), and higher ceruloplasmin predicted worse impairment (higher cGDS values,
p
< 0.01). In the subgroup with undetectable viral load and minimal comorbidity, CSF ceruloplasmin and haptoglobin were strongly associated with GDS impairment (ORs 5.57 and 2.96, respectively; both
p
< 0.01) and HAND (both
p
< 0.01). Concurrently measured CSF IL-6 and TNF-α were only weakly correlated to these three biomarkers. Higher CSF ceruloplasmin, haptoglobin, and VEGF are associated with a significantly greater likelihood of HAND, suggesting that interventions aimed at disordered iron transport and angiogenesis may be beneficial in this disorder.
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