Scott R. Evans

The prevalence and incidence of neurocognitive impairment in the HAART era.

Objectives:HAART suppresses HIV viral replication and restores immune function. The effects of HAART on neurological disease are less well understood. The aim of this study was to assess the prevalence and incidence of neurocognitive impairment in individuals who initiated HAART as part of an AIDS clinical trial. Design:A prospective cohort study of HIV-positive patients enrolled in randomized antiretroviral trials, the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study. Methods:We examined the association between baseline and demographic characteristics and neurocognitive impairment among 1160 subjects enrolled in the ALLRT study. Results:A history of immunosuppression (nadir CD4 cell count < 200 cells/μl) was associated with an increase in prevalent neurocognitive impairment. There were no significant virological and immunological predictors of incident neurocognitive impairment. Current immune status (low CD4 cell count) was associated with sustained prevalent impairment. Conclusion:The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

Impact of Combination Antiretroviral Therapy on Cerebrospinal Fluid HIV RNA and Neurocognitive Performance

Objective:To determine whether antiretroviral regimens with good central nervous system (CNS) penetration control HIV in cerebrospinal fluid (CSF) and improve cognition. Design:Multisite longitudinal observational study. Setting:Research clinics. Study participants:One hundred and one individuals with advanced HIV beginning or changing a new potent antiretroviral regimen were enrolled in the study. Data for 79 participants were analyzed. Participants underwent structured history and neurological examination, venipuncture, lumbar puncture, and neuropsychological tests at entry, 24, and 52 weeks. Intervention:Antiretroviral regimens were categorized as CNS penetration effectiveness (CPE) rank of at least 2 or less than 2. Generalized estimating equations were used to examine associations over the course of the study. Main outcome measures:Concentration of HIV RNA in CSF and blood and neuropsychological test scores (NPZ4 and NPZ8). Results:Odds of suppression of CSF HIV RNA were higher when CPE rank was at least 2 than when it was less than 2. Odds of suppression of plasma HIV RNA were not associated with CPE rank. Among participants with impaired neuropsychological performance at entry, those prescribed regimens with a CPE rank of at least 2 or more antiretrovirals had lower composite NPZ4 scores over the course of the study. Conclusion:Antiretroviral regimens with good CNS penetration, as assessed by CPE rank, are more effective in controlling CSF (and presumably CNS) viral replication than regimens with poorer penetration. In this study, antiretrovirals with good CNS penetration were associated with poorer neurocognitive performance. A larger controlled trial is required before any conclusions regarding the influence of specific antiretrovirals on neurocognitive performance should be made.

Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals

Context Neurologic toxicity is the most commonly reported adverse effect of the antiretroviral drug efavirenz. Contribution In this substudy of a randomized, controlled trial, 12 of 200 (6%) HIV-infected individuals discontinued treatment with efavirenz because of central nervous system symptoms or mood disorders versus 0 of 103 individuals (0%) who were not receiving the drug. Although patients taking efavirenz had more neuropsychological symptoms, such as bad dreams, in the first week of therapy, no statistically significant neuropsychological differences were found at weeks 4, 12, and 24. Implications Some adverse neuropsychological effects associated with efavirenz are probably transient. The Editors Efavirenz is a non-nucleoside reverse transcriptase inhibitor approved for treatment of HIV infection. The drug is potent, is generally well tolerated, and can be administered once daily, making it a preferred treatment option for HIV infection (1, 2). The most commonly reported adverse effect with efavirenz is neurologic toxicity, with more than 50% of patients reporting symptoms in open-label studies (1, 3). Our randomized, controlled study prospectively characterized aspects of the neurologic toxicity of 3 protease inhibitorsparing antiretroviral regimens for the initial treatment of HIV infection. Methods This investigator-initiated trial was a substudy of the AIDS Clinical Trials Group study A5095, a randomized, double-blind trial of 3 antiretroviral regimens: zidovudine and lamivudine in combination with efavirenz; abacavir; or abacavir and efavirenz in combination (4). For simplicity, we will refer to 2 groups: patients who received efavirenz (with or without abacavir) and those who did not. Randomization was performed centrally without reference to center. The study was supported by the National Institutes of Health (NIH) and was approved by the institutional review boards at each of the participating institutions, with each patient providing informed consent to participate in the substudy. All patients at sites taking part in the substudy were invited to participate before randomization for the parent study (Figure 1). Unblinding and within-class substitutions were allowed in cases of treatment-limiting toxicity (we substituted stavudine for zidovudine, didanosine for abacavir, and nevirapine for efavirenz). Participants had not previously received antiretroviral therapy, and their baseline plasma HIV-1 RNA levels were greater than 400 copies/mL. Parent study A5095 enrolled 1147 participants, of whom 303 at 36 clinical trials units volunteered to participate in the additional evaluations for A5097s. Participants were recruited between March 2001 and January 2002. Figure 1. CONSORT diagram of substudy 5097s. The primary measures of neuropsychological performance were the Trail Making Tests (Parts A and B) and the Digit Symbol Substitution Test (part of the Wechsler Adult Intelligence Scale III [5]). A summary neuropsychological Z score (NPZ3) was derived from the sum of the scores from these 3 tests and standardized for age. Positive scores indicated above-normal function, whereas negative scores indicated below-normal function. The entire score was coded as missing if any component of the NPZ3 was not available. The Neurologic AIDS Research Consortium provided administrator training at each site. These tests assessed functioning in the areas of motor persistence, sustained attention, response speed, visuomotor coordination, and conceptual shifting and tracking. Neuropsychometric measures were collected at baseline and at weeks 1, 4, 12, and 24. Testing was performed at each time point to assess symptoms that might be associated with efavirenz use, sleep disorders, anxiety, depression, and history of drug abuse. The instruments are summarized in Table 1. The symptom questionnaire developed for this study is shown in the Appendix Figure. Appendix Figure. Sample participant questionnaire. Table 1. Testing Instruments Whole blood was collected from all participants to determine efavirenz trough concentrations in plasma (13). These data were used to explore relationships between drug exposure and other variables that were evaluated in the study. Statistical Analysis Our substudy was designed to compare neurologic changes from baseline in patients who received efavirenz with changes in those who did not. The study had 90% power to detect a standard deviation of 0.4 for change in the summary neuropsychological performance score from baseline to week 1. We presented descriptive statistics for the study sample and used nonparametric tests to determine treatment differences. Using the nonparametric methods of Hodges and Lehmann (14) and Proc-StatXact software, version 4.0.1 (Cytel Software Corp., Cambridge, Massachusetts), we estimated treatment differences for continuous outcomes with corresponding exact confidence intervals. Generalized estimating equation modeling (a regression method) and the Wei-Johnson test (a nonparametric method for analyzing incomplete 2-sample data) (15) were used to compare treatment groups longitudinally; both methods assumed that data were missing completely at random. We used the Spearman correlation coefficient, a rank-based method that is robust to extreme observations, to evaluate correlations. All significance testing was performed at an level of 0.05 with no adjustment for multiple testing. All reported P values were 2-sided. To assess the potential effect of any missing data, we performed multiple imputation, analyzed 2 worst-case scenarios (Appendix Table 1 and Appendix Table 2), and conducted an as-treated analysis that excluded patients who discontinued efavirenz therapy. We used SAS software (SAS Institute, Inc., Cary, North Carolina) to perform statistical analyses. Test sources included Elsevier Science (Oxford, United Kingdom) for the Pittsburgh Sleep Quality Index, Mind Garden (Redwood City, California) for the State-Trait Anxiety Inventory for Adults, and the National Institute of Mental Health (Bethesda, Maryland) for the Center for Epidemiologic Studies Depression Scale. Role of the Funding Sources This investigator-initiated protocol was supported by the NIH. Drugs used in the study were donated by pharmaceutical companies whose representatives participated in team discussions. The study was monitored by NIH-contracted monitors and was supervised by a data safety monitoring committee that was appointed by the National Institute of Allergy and Infectious Diseases. The NIH-supported biostatistical team working with the AIDS Clinical Trials Group and the Neurologic AIDS Research Consortium performed the statistical analyses. The protocol team, led by the first author, had final responsibility for the study protocol, case report forms, statistical analysis plan, progress of the study, analysis, and reporting of the data, regardless of outcome. The final version was the sole responsibility of the authors. The team had full access to the data files of the study. Results Baseline Evaluations Recruitment characteristics are displayed in Figure 1; demographic characteristics of the study participants are presented in Table 2. The treatment groups were balanced at baseline with respect to demographic characteristics, neuropsychological measures, and responses to the symptom questionnaire. The sleep disturbance component of the global sleep index demonstrated a baseline difference; the patients who eventually received efavirenz had marginally more sleep disturbances (P= 0.048) (data not shown). Other components of the sleep index, including quality, latency, duration, efficiency, use of sleeping medication, and daytime dysfunction, were similar between groups. Alcohol abuse, drug use, and affective disturbances were infrequent and similar for both groups. Table 2. Baseline Characteristics and Evaluations by Treatment Group Disposition of Study Participants The study allowed for drug substitution from the same class of antiretroviral agents in cases of treatment-limiting toxicity. Table 3 summarizes the modifications that occurred and the respective reasons. Appendix Table 3 gives further details of timing of modifications and the ethnicity of the individuals. Primary end point data (the change in NPZ3 from baseline to week 1) were observed in 283 of the 303 (93.4%) participants. Table 3. Reasons for Modification of Treatment Appendix Table 1. Neuropsychological Performance Appendix Table 2. Results of Sensitivity Analysis by Generalized Estimating Equation Method Appendix Table 3. Status and Ethnicity of Patients Requiring Modification of Treatment Prospective Evaluations Median NPZ3 scores improved in both groups during the study, with the greatest change occurring in the first week of treatment (Figure 2). No statistically significant differences in changes in neuropsychological performance were observed between the groups at any time point. We conducted conventional longitudinal analyses to further investigate differences in neuropsychological scores between the treatment groups. On the basis of these analyses, we had insufficient evidence to conclude that there were treatment differences (generalized estimating equation modeling in which treatment was the only independent variable and an exchangeable correlation structure was assumed, P= 0.176; Wei-Johnson test, P= 0.196). Multiple sensitivity analyses were performed, including single and multiple imputation methods, as-treated analyses, and 2 forms of worst-case scenarios. Details of these analyses are shown in Appendix Table 1. Multiple imputation and as-treated analyses generally provided similar results to observed data at specific weeks; however, the worst-case analyses at weeks 4, 12, and 24 displayed significant differences between groups. These results suggest that differences between groups might exist if the worst-case scenario were true, that is, if patients without data who were receiving efavirenz had wors

Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort

Objective:Differences in antiretroviral distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of antiretroviral therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive participants with plasma HIV-1 RNA (vRNA) suppression. Design:Participants with at least 6 weeks ongoing antiretroviral drug use and vRNA less than 50 copies/ml (N = 2636; 83% male, median baseline CD4 T cells: 244 cells/μl) had at least one neuroscreen assessment [Trail Making Test, Part A and B; Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol] at 10 413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). Central nervous system penetration effectiveness (CPE) ranks of 0.0 (low), 0.5 (medium), or 1.0 (high) were assigned to antiretrovirals and summed per regimen, per neurovisit. Methods:Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to antiretroviral regimen. Covariates were retained if P ≤ 0.1. Results:A final model demonstrated that better NPZ3 scores were associated with higher CPE among participants taking more than three antiretroviral drugs (+0.07 per one unit increase in CPE score; P = 0.004) but not among participants with three or less antiretroviral drugs in the regimen (+0.01; P = 0.5). Results were adjusted for demographics, injection drug use, hepatitis C virus serostatus, CD4 cell count (current and nadir), baseline vRNA, antiretroviral experience, and years since first antiretroviral drug use. Conclusion:Use of antiretroviral drugs with better estimated CNS penetration may be associated with better neurocognitive functioning; some people may require more than three antiretroviral drugs to treat HIV in the CNS. Clinically this means antiretroviral regimens could be designed to optimize estimated CNS penetration without sacrificing virologic and immunologic benefits.

Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects.

Objectives: The impact of highly active antiretroviral therapy (HAART) on hepatitis C virus (HCV) is unknown. We analysed changes in HCV RNA and the frequency of hepatotoxicity in co-infected patient enrolling in AIDS Clinical Trials Group trials, and determined whether HCV impairs successful immune reconstitution in these populations. Design/methods: In a prospective analysis of co-infected patients completing at least 16 weeks of HAART in four trials, and co-infected patients with available stored plasma from two other completed HAART trials, HCV RNA was measured at baseline and to week 48. A retrospective analysis of immune recovery in 40 HCV-RNA-positive and 129 HCV-RNA-negative patients from a single trial was performed. Results: Prospective analysis: 60 patients completed at least 16 weeks of HAART. The mean HCV-RNA level increased 0.35 log10 IU/ml at week 16 and 0.43 log10 IU/ml at week 48. When stratified by baseline CD4 cell count, subjects’ HCV-RNA levels increased 0.43 and 0.59 log10 IU/ml at weeks 16 and 48 for entry CD4 cell counts < 350 cells/mm3, but only 0.26 and 0.1 log10 IU/ml at weeks 16 and 48 for entry CD4 cell counts > 350 cells/mm3. Severe alanine aminotransferase elevations occurred in only 3.3%. Retrospective analysis: HCV co-infection had no effect on the overall mean CD4 cell increase at weeks 16 or 48 compared with uninfected controls. Conclusion: In HCV-co-infected patients undergoing HAART, immune recovery is associated with a persistent increase in HCV RNA, especially with baseline CD4 cell counts < 350 cells/mm3. HCV co-infection did not antagonize the CD4 cell response to HAART.

Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort.

Objective: Prior studies have shown improved neurocognition with initiation of antiretroviral treatment (ART) in HIV. We hypothesized that stopping ART would be associated with poorer neurocognitive function. Methods: Neurocognitive function was assessed as part of ACTG 5170, a multicenter, prospective observational study of HIV-infected subjects who elected to discontinue ART. Eligible subjects had CD4 count >350 cells/mm3, had HIV RNA viral load <55,000 cp/mL, and were on ART (≥2 drugs) for ≥6 months. Subjects stopped ART at study entry and were followed for 96 weeks with a neurocognitive examination. Results: A total of 167 subjects enrolled with a median nadir CD4 of 436 cells/mm3 and 4.5 median years on ART. Significant improvements in mean neuropsychological scores of 0.22, 0.39, 0.53, and 0.74 were found at weeks 24, 48, 72, and 96 (all p < 0.001). In the 46 subjects who restarted ART prior to week 96, no significant changes in neurocognitive function were observed. Conclusion: Subjects with preserved immune function found that neurocognition improved significantly following antiretroviral treatment (ART) discontinuation. The balance between the neurocognitive cost of untreated HIV viremia and the possible toxicities of ART require consideration. Classification of evidence: This study provides Class III evidence that discontinuing ART is associated with an improvement in 2 neuropsychological tests (Trail-Making Test A & B and the Wechsler Adult Intelligence Scale–Revised Digit Symbol subtest) for up to 96 weeks. Resuming ART was not associated with a decline in these scores for up to 45 weeks.

HIV neuropathy natural history cohort study: assessment measures and risk factors.

Background: Distal sensory polyneuropathy (DSP) is the most common neurologic complication of human immunodeficiency virus (HIV) infection. Risk factors for DSP have not been adequately defined in the era of highly active antiretroviral therapy. Methods: The authors evaluated 101 subjects with advanced HIV infection over 48 weeks. Assessments included a brief peripheral neuropathy (PN) screen (BPNS), neurologic examination, nerve conduction studies, quantitative sensory testing (QST), and skin biopsies with quantitation of epidermal nerve fiber density. Data were summed into a Total Neuropathy Score (TNS). The presence, severity, and progression of DSP were related to clinical and laboratory results. Results: The mean TNS (range 0 to 36) was 8.9, with 38% of subjects classified as PN-free, 10% classified as having asymptomatic DSP, and 52% classified as having symptomatic DSP. Progression in TNS from baseline to week 48 occurred only in the PN-free group at baseline (mean TNS change = 1.16 ± 2.76, p = 0.03). Factors associated with progression in TNS were lower current TNS, distal epidermal denervation, and white race. As compared with the TNS diagnosis of PN at baseline, the BPNS had a sensitivity of 34.9% and a specificity of 89.5%. Conclusions: In this cohort of advanced human immunodeficiency virus (HIV)–infected subjects, distal sensory polyneuropathy was common and relatively stable over 48 weeks. Previously established risk factors, including CD4 cell count, plasma HIV RNA, and use of dideoxynucleoside antiretrovirals were not predictive of the progression of distal sensory polyneuropathy (DSP). Distal epidermal denervation was associated with worsening of DSP. As compared with the Total Neuropathy Score, the brief peripheral neuropathy screen had relatively low sensitivity and high specificity for the diagnosis of DSP.

Peripheral neuropathy in HIV: prevalence and risk factors.

Objectives:To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART. Design:AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally. Methods:Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations. Results:Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/μl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use. Conclusion:Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN.

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

BACKGROUND Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia. METHODS We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. RESULTS During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%. CONCLUSIONS In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01994720.).

Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy

Objective: To demonstrate the relationship between epidermal nerve fiber density (ENFD) in the leg and the phenotype of HIV-associated distal sensory polyneuropathy (HIV-DSP) in a multicenter prospective study (ACTG A5117). Methods: A total of 101 HIV-infected adults, with CD4 cell count <300 cells/mm3 and who had received antiretroviral therapy (ART) for at least 15 consecutive weeks, underwent standardized clinical and electrophysiologic assessment. All 101 subjects were biopsied at the distal leg (DL) and 99 at the proximal thigh (PT) at baseline. ENFD was assessed by skin biopsy using PGP9.5 immunostaining. Associations of ENFD with demographics, ART treatment, Total Neuropathy Score (TNS), sural sensory nerve action potential (SNAP) amplitude and conduction velocity, quantitative sensory testing (QST) measures, and neuropathic pain were explored. Results: ENFD at the DL site correlated with neuropathy severity as gauged by TNS (p < 0.01), the level of neuropathic pain quantified by the Gracely Pain Scale (GPS) (p = 0.01) and Visual Analogue Scale (VAS) (p = 0.01), sural SNAP amplitude (p < 0.01), and toe cooling (p < 0.01) and vibration (p = 0.02) detection thresholds. ENFD did not correlate with neurotoxic ART exposure, CD4 cell count, or plasma HIV-1 viral load. Conclusions: In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.