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  16th CROI
Conference on Retroviruses and Opportunistic Infections Montreal, Canada
February 8-11, 2009
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Cognitive Impairment & Neuropathy Persist Despite HAART and Are Associated With Metabolic Syndrome
  Reported by Jules Levin
CROI 2009 Feb 8-12 Montreal
There are several abstracts below in this email and immediately below a link to another report on neurological disorders. In sum, despite HAART the prevalence of cognitive dysfunction and neuropathy persists, and two reports at CROI find elements of metabolic dysfunction are associated with both cognitive dysfunction and neuropathy. These findings are not unexpected and have been observed in the literature in published studies. In the general population it has been reported the diabetes and other metabolic conditions are associated with increased risk for cognitive disorders and neuropathy as well. Despite HAART and immune reconstruction the prevalance of cognitive dysfunction persists. It appears that there is variability between patients regarding cognitive disorders. Short term benefit to cognitive function may result after starting HAART while longer term effects may not. Some patients may benefit from HAART while others may not. I'm sure there are a number of risk factors. At CROI and in previously published studies nadir CD4 can be associated with developing neuropathy and cognitive disorders. So if a patient started HAART when their CD4 was 70 that immediately puts them at risk for developing neuropathy and cognitive dysfunction as well as lipodystrophy. Of course these points all support considering starting earlier HAART. It is clearly crucial to manage metabolic conditions optimally to prevent cognitive disorders and to prevent neuropathy from worsening. Inteventions for cognitive disorders are another story, we don't have any and this must be addressed. Another point that is clearly important is the role of HIV. Two studies support that HIV prematurely ages the immune system and I think likely leads to increased risk for aging-associated conditions including inflammation, so researchers MUST begin to try to understand this and look for interventions. Jules
Neurocognitive Disorders Threaten HIV+ - (02/20/09)
Contributions of Metabolic Syndrome to Neurocognitive Impairment: diabetes & waist size are associated in this study with cognitive impairment Allen McCutchan*1, J Marquie-Beck1, S Letendre1, R Heaton1, T Wolfson1, D Rosario1, T Alexander1, C Marra2, B Ances3, I Grant1, and the CHARTER Group 1Univ of California, San Diego, US; 2Univ of Washington, Seattle, US; and 3Washington Univ, St Louis, MO, US
Background: While combination ART (cART) has prolonged survival in HIV+ patients, a high prevalence of neurocognitive impairment (NCI) has persisted and cART-related metabolic syndrome has emerged as a complication. We studied the relationship of NCI and metabolic syndrome in HIV-infected participants in CHARTER, an observational study at academic clinics in the 6 US cities.
Methods: In a cross-sectional substudy, 145 HIV-infected participants were selected from 1534 enrolled in CHARTER based on their provision of a fasting blood sample. NCI was defined as global deficit score ≥0.5 based on a battery of neuropsychological tests that adjust for age-, education-, and race-specific norms and are validated to detect HIV-related impairment. Effects on NCI of demographics (age, gender, education, race/ethnicity), biomarkers of HIV disease (current and nadir CD4 count, plasma HIV levels, and AIDS diagnosis), antiretroviral (ARV) history, and metabolic syndrome-related variables (clinical history of type II diabetes), body mass index, waist circumference, blood pressure, glucose, insulin, insulin resistance, triglycerides, high- and low-density lipoproteins cholesterol (LDL-C), and serum leptin were tested in uni- and multi-variate models.
Results: Substudy participants were mostly white (58%) and male (86%) and averaged 46 years old. Prevalence of NCI was 53 of 145 (37%), consistent with other estimates in the HAART era. In univariate models, the only demographic variable that correlated with NCI was less education (12.6 vs 13.4 years, p <0.05). Of the metabolic syndrome-related variables, correlates of NCI included greater waist circumference (98 vs 90 cm, p <0.05), lower LDL-C (89 vs 106 mg/dL, p <0.01), and higher prevalence of type II diabetes (16 vs 2%, p <0.01). In multivariate logistic regression analysis (n = 84), waist circumference (OR = 1.06/cm), type II diabetes (OR = 13), and AIDS (OR = 89), but not LDL-C or other metabolic factors, were significantly increased in those with NCI (p <0.01 for all 3).
Conclusions: Of components of the metabolic syndrome, only waist size and diabetes correlated with higher risk of NCI. Insulin resistance, a strong correlate of diabetes type II, was not increased in NCI (from Jules: I recall published studies in the literature finding insulin resistance associated with cognitive dysfunction in the general population). Diabetes, but not waist size, has been previously correlated with cognitive impairment in HIV-infected populations, but the mechanism(s) are unclear. Weight reduction and ARV drugs that are less likely to induce metabolic syndrome and diabetes might help to protect the brain.
High Frequency of Neurocognitive Disorders in Older HIV-infected Patients despite a Sustained Virological and Immunological Response on cART: The Sigma Study
A Dulioust1, N Lerolle1, P Dolphin1, F Boufassa2, M Duracinsky1, J-F Delfraissy1, C Goujard1, and Jacques Gasnault*1 1Bicetre Hospital, APHP, Le Kremlin Bicetre, France and 2INSERM U822, Univ Paris Sud XI, Le Kremlin Bicetre
Background: During aging, HIV infection could accelerate the emergence of cognitive disorders, despite the widespread use of virologically effective combination ART (cART).
Methods: We report here the neurocognitive subset (Neurosigma) of the Sigma study, an observational, cross-sectional study designed to describe the medical conditions and the psychosocial status of patients aged 60 years and more in the Bicetre HIV Cohort, a hospital cohort of 1350 HIV-infected patients. Demographic data, medical and therapeutic history, cardiovascular risk (CVR), plasma HIV RNA levels, and CD4 counts since HIV diagnosis were collected. Subjects with active neurologic or psychiatric diseases and low educational level were excluded. Subjects underwent a brief neuropsychological exam using the Trailmaking A/B and the Digit Symbol yielding a composite NPZ3 score (assessing psychomotor speed, attention, cognitive sequencing, and shifting cognitive sets). The Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Instrumental Activity of Daily Living (IADL) were performed.
Results: Among the 66 patients older than 60 years, 37 (56%) achieved the Neurosigma substudy. At enrolment, all patients except 1 were treated with cART; 73% were men. Median age was 67 years (range 60 to 84). Median duration of HIV infection and of ART were respectively 11 (IQR 5 to 17) and 10 (IQR 3 to 14) years. Median nadir CD4 count was 113 cells/μL (IQR 80 to 239), whereas the last median CD4 count was 522 cells/μL (IQR 443 to 675). HIV RNA was <50 copies/mL in all treated patients. One or more CVR factors was present in 27 patients (diabetes 27%, hypertension 49%, dyslipidemia 43%). A neurocognitive impairment was detected in 19 patients (51%). MMSE was abnormal (<-1.65 SD) in 6 (16%) patients. Severe impairment (<-2) of NPZ3 was observed in 11 patients (30%) including 4 with abnormal IADL and mild (-2≦NPZ3<-1) in 8 (21%). GDS was abnormal (>5) in 7 patients (19%).
Conclusions: Despite a sustained response to cART, neurocognitive disorders are more frequent in old HIV+ patients than in the general aging population, but are underdiagnosed by their physicians. In our patients, subcortical types of cognitive impairment remain more predominant than neocortical types. The respective role of HIV, ART, and co-morbidities is debated. Longitudinal studies are needed to assess the outcome of these disorders in aging and to determine their predictive factors.
Persisting (57%) High Prevalence of HIV Distal Sensory Peripheral Neuropathy in the Era of Combination ART: Correlates in the CHARTER Study
Ronald Ellis*1, D Rosario1, D Clifford2, J McArthur3, D Simpson4, T Alexander1, B Gelman5, and I Grant1 1Univ of California, San Diego, US; 2Washington Univ, St Louis, MO, US; 3Johns Hopkins Univ, Baltimore, MD, US; 4Mt Sinai Sch of Med, New York, NY, US; and 5Univ of Texas Med Branch, Galveston, US
Background: Before the advent of combination ART (cART), HIV distal sensory polyneuropathy (DSPN) was frequent, its clinical impact high and dideoxynucleoside-containing drugs contributed significantly to the problem. Improvements in ART have transformed HIV from a fatal to a chronic, manageable disease, while reducing toxicities. Our objective was to provide updated estimates of the prevalence and clinical effect of DSPN in the cART era.
Methods: Baseline prevalence of DSPN and clinical correlates were assessed in 1539 HIV-infected individuals enrolled in a prospective, observational study at 6 US sites. DSPN was defined as at least 1 clinical sign in a symmetrical, bilateral pattern on neurological exam. Signs included diminished distal vibratory sensation, inability to discriminate sharp from dull, and reduced ankle reflexes. Correlates of DSPN evaluated in uni- and multivariate models were age, cART and dideoxynucleoside-containing drug use, HIV disease markers (current and nadir CD4, plasma viral load), hepatitis C virus (HCV), and substance use disorders (alcohol, opiates). Pain and its effect on quality of life were assessed using the MOS-HIV Health Survey.
Results: DSPN prevalence was 57% (881 of 1539).. DSPN subjects experienced more pain (219 of 881 [25%] vs 53 of 658 [8%]; p <0.01) and were significantly more impaired in MOS pain function scores (median [interquartile range], 66 [44 to 89] vs 78 [44 to 89]; p <0.01) and overall physical health (43 [33 to 54] vs 49 [39 to 58]; p <0.01) compared to those without DSPN. DSPN was more common in those currently taking cART (711 of 1095 [65%]) as compared to ARV-naïve subjects (71 of 234 [30%]) or to those who previously took ARV but stopped (99 of 210 [47%]). Among cART-treated subjects with DSPN, 68% (483) had been exposed to dideoxynucleoside-containing drugs (median exposure 41 months [17 to 72]). In multivariate analysis, significant predictors of DSPN included older age (OR 2.1 per 10-year increase, 95%CI 1.8 to 2.4), lower CD4 nadir (OR 1.2 per 100 cell decrease, 95%CI 1.1 to 1.2), current ARV use (OR 1.6, 95%CI 1.5 to 1.7), past dideoxynucleoside-containing drug use (OR 1.9, 95%CI 1.7 to 2.2), and history of opiate abuse or dependence (OR 1.4, 95%CI 1.3 to 1.4) (n = 267; median years since last met criteria 6 [0.9 to 15]).
Conclusions: DSPN remains highly prevalent in the era of cART. Neuropathic pain leads to substantial self-reported disability, reduced quality of life and a need for costly analgesic medications that increase the burden of treatment, raising the potential for adverse drug-drug interactions. In addition to HIV and cART, advancing age, and co-morbidities such as opiate abuse may amplify the clinical impact of DSPN. (from Jules: neuropathy can increase risk for failing as people age and thus increase risk for fractures particularly because people with HIV have high prevalence rates of osteopenia and osteoporosis
HIV-associated Peripheral Neuropathy in the HAART Era: Results from AIDS Clinical Trials Group Longitudinal Linked Randomized Trials Protocol A5001

Scott Evans*1, D Clifford2, H Chen1, G Schifitto3, T-M Yeh1, K Wu1, R Bosch1, J McArthur4, D Simpson5, and R Ellis6 1Harvard Sch of Publ Hlth, Boston, MA, US; 2Washington Univ, St Louis, MO, US; 3Univ of Rochester, NY, US; 4Johns Hopkins Univ, Baltimore, MD, US; 5Mt Sinai Sch of Med, New York, NY, US; and 6Univ of California, San Diego, US
Background: Peripheral neuropathy (PN) is the most frequent neurological complication in HIV infection. Symptoms including pain, numbness, and "pins and needles" sensation, affect quality of life, often require analgesic therapy, and may influence the choice of antiretroviral (ARV) drugs. No FDA-approved therapy exists. While pre-HAART risk factors for PN included high HIV-1 RNA, low CD4, and neurotoxic ARV (n-ARV) use, risk factors in the HAART era are not well delineated. Objectives of this study include estimating the prevalence of neuropathic signs and symptoms with ARV initiation in ARV-naïve patients and investigating prognostic factors in the HAART era.
Methods: Participants from the AIDS Clinical Trials Group (ACTG) A5001 cohort that initiated HAART in randomized trials for ARV-naïve patients were annually administered a brief PN screen by trained site personnel, evaluating symptoms and signs of PN between January 2000 and June 2007. HIV-1 RNA, CD4, n-ARV and PI use were concurrently collected longitudinally. PN was defined as at least mild loss of vibration sensation in both great toes bilaterally or absent or hypoactive ankle reflexes bilaterally relative to knees. Symptomatic PN (SPN) was defined as PN plus bilateral symptoms. Multivariable logistic generalized estimating equation regression models were used to estimate associations with PN and SPN while controlling for potential confounders.
Results: We analyzed 2135 naïve participants (81% male, 44% white, 32% black, median age 39, median log HIV-1 RNA at HAART initiation 4.9). n-ARV use peaked at week 144 (25%) dropping to 10.9% at week 384. The increasing prevalence of PN and SPN after HAART initiation are summarized below:


Notable factors associated with PN include: years since ARV-initiation (p <0.01, OR 1.09 for each additional year, 95%CI 1.06, 1.12), age (p <0.01, OR = 1.89 for a 10-year increase, 95%CI 1.73, 2.07), and n-ARV use (p = <0.01, OR = 1.50, [1.29, 1.75]).
Conclusions: The prevalence of PN and SPN increases with time after ARV initiation in ARV-naïve patients despite increased virologic control and immune function, and the decline of n-ARV use. Age and n-ARV use are notable risk factors for N and SPN.
Metabolic Syndrome Components as Risk Factors for Distal Sensory Polyneuropathy Beau Ances*1, D Rosario2, F Vaida2, J Marquie-Beck2, R Ellis2, D Simpson3, D Clifford1, J McArthur4, I Grant2, A McCutchan2, and CNS HIV ART Effects Res Metabolic Study Group

1Washington Univ Sch of Med, St Louis, MO, US; 2Univ of California, San Diego Sch of Med, US; 3Mt Sinai Sch of Med, New York, NY, US; and 4Johns Hopkins Univ Sch of Med, Baltimore, MD, US
Background: Combination ART (cART) can induce metabolic syndrome, a cluster of risk factors that increase atherosclerosis. Distal sensory polyneuropathy (DSPN) is the most common peripheral nervous system complication of HIV and cART. We studied the relationship between metabolic syndrome and HIV-associated DSPN in a cohort of HIV+ participants followed by Central nervous system (CNS) HIV ART Research (CHARTER) from 2003 to 2007.
Methods: From 1556 participants recruited in 6 US cities, a subgroup of 130 HIV+ participants who had fasting laboratory tests were neurologically assessed for DSPN, defined as decreased reflexes or sensation in the lower legs. Metabolic syndrome components included elevated blood pressure (mean arterial pressure ≥100 mmHg), dyslipidemia (triglycerides ≥150 mg/dL and high-density lipoprotein cholesterol <40 mg/dL), central obesity (body mass index > 30 kg/m2), glucose intolerance (plasma glucose ≥ 110 mg/dL], and type 2 diabetes. Metabolic syndrome was defined by the presence of ≥3 of these criteria. A logarithmic transformation of each metabolic syndrome component was used due to skewness and unequal variance. A multivariate logistic regression controlling for other DSPN risks factors examined associations between DSPN and each metabolic syndrome component as a continuous variable.
Results: In the subgroup (n = 130), metabolic syndrome and DSPN were not related (Pearson's χ2 test = 0.69). Furthermore, after controlling for age, CD4 current, length of HIV infection, duration of drug use, and past protease inhibitor use in a multivariate model, Metabolic syndrome did not help predict DSPN. When each Metabolic syndrome component was assessed, only triglycerides were a significant risk factor for DSPN. In the entire cohort (n = 1556), DSPN correlated with self-reported type 2 diabetes (OR = 2.3, p <0.01).
Conclusions: The risk of HIV-associated DSPN was increased by diabetes and hypertriglyceridemia, but not by other metabolic syndrome components. These components increase the risk of DSPN in HIV-uninfected persons as well, so whether or not they interact with HIV to provide additional risk remains unclear.