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Background: In the setting of severe immunosuppression, the polyomavirus JC (JCV) can cause a lytic infection of oligodendrocytes. This demyelinating disease of the CNS white matter (WM) is called progressive multifocal leukoencephalopathy (PML). JCV has a very narrow host-cell range and productive infection of neurons has never been demonstrated. Patient, methods, and results: An HIV-1-infected patient presented with signs of pyramidal tract and cerebellar dysfunction. Brain MRI revealed T2 hyperintensities in the WM of both frontal lobes and cerebellar atrophy. His disease progressed despite therapy and he died 6 months later. In addition to classic PML findings in the frontal lobe WM, autopsy revealed scattered foci of tissue destruction in the internal granule cell layer (IGCL) of the cerebellum. In these foci, enlarged granule cell neurons identified by the neuronal markers MAP-2 and NeuN reacted with antibodies specific for the polyomavirus VP1 capsid protein. Electron microscopy showed 40 nm viral particles, consistent with polyomaviruses, in these granule cell neurons. In addition, JCV DNA was detected by PCR after laser capture microdissection of cells from the areas of focal cell loss. Finally, in situ hybridization studies demonstrated that many granule cell neurons were infected with JCV but did not contain viral proteins. Sequence analysis of the JCV regulatory region from cerebellar virions showed a tandem repeat pattern also found in PML lesions of the frontal lobe WM. Conclusion: JCV can productively infect granule cell neurons of the IGCL of the cerebellum. This suggests a role for JCV infection of neurons in cerebellar atrophy occurring in HIV-infected individuals.

The etiology of the lymphadenopathy and follicular hyperplasia associated with human immunodeficiency virus type 1 (HIV-1) infection has remained unclear. To determine whether the B-lymphocyte expansions characteristic of this syndrome represent polyclonal and virus-specific processes, the antigen specificity of B cells in lymphoid tissues of monkeys infected with simian-human immunodeficiency virus (SHIV) chimeras was assessed using an inverse immunohistochemical assay with biotinylated HIV-1 envelope gp120 (Env) as an antigen probe. Env-binding B cells were found aggregated in lymph node and splenic germinal centers (GCs). Most Env-binding GCs also contained an unstained population of B cells, suggesting the GCs were formed by a polyclonal (oligoclonal) process. By day 42 following infection, Env-binding B cells were present in 19% of all lymph node GCs. Env-binding cells were present in 25% of GCs even during chronic infection. This extraordinarily high frequency of Env-specific B lymphocytes suggests that the expansion of virus-specific B cells may largely account for the follicular hyperplasia in AIDS virus-infected individuals.

Background/objectives Alemtuzumab is approved in over 30 countries for relapsing-remitting multiple sclerosis. In the 2-year, phase 3 CARE-MS II study (NCT00548405), alemtuzumab had superior efficacy over subcutaneous interferon beta-1a and manageable safety over 2 years; follow-up at Year 3 showed durable efficacy of alemtuzumab. Here we report results for years 3 and 4 after alemtuzumab initiation, and for years 1 and 2 after alemtuzumab initiation in patients initially treated with subcutaneous interferon beta-1a (crossover cohort). Design and methods In CARE-MS II, patients with active relapsing-remitting multiple sclerosis who relapsed on prior therapy received 2 courses of alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or subcutaneous interferon beta-1a (44 ?g 3 times/week). In the extension study (NCT00930553), alemtuzumab-treated patients could receive as-needed re-treatment (12 mg/day intravenously on 3 consecutive days) ?1 year apart or other disease-modifying therapy. Crossover patients received 2 alemtuzumab courses (5 days then 3 days) 12 months apart. Results The extension enrolled 393 (93%) eligible patients from the core study alemtuzumab arm. Through 4 years, 68% received the first 2, but no additional courses; 24% and 7% received 1 or 2 additional courses, respectively; 5% received another disease-modifying therapy during the extension. Twenty-five patients (6%) discontinued study, none from adverse events. Among former interferon beta-1a patients, 146 (83%) entered the extension; 131 (90%) received 2 alemtuzumab courses. Seven extension withdrawals (5%) occurred in crossover patients, 1 from an adverse event. Efficacy and safety data will be reported. Conclusions Most patients receiving alemtuzumab in the core study required no re-treatment during the first 2 extension years; few received alternative therapies or withdrew from study. Among crossover patients, most received both treatment courses and remained in the study.

Objective: Evaluate the effect of alemtuzumab on relapse and disability versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients who have relapsed on prior therapy. Background Alemtuzumab was significantly more effective than SC IFNB-1a in two clinical trials with treatment-naive RRMS patients. Treatment options are limited for RRMS patients experiencing disease activity during therapy, and few controlled studies have been conducted to determine their appropriate management. Design/Methods: CARE-MS II is a 2-year rater-blinded trial with RRMS patients who have relapsed during prior therapy. Alemtuzumab treatment was 12 mg/day (or 24 mg/day in an exploratory cohort) by intravenous administration for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly throughout the study. Entry criteria included 18-55 years of age, MS symptom onset within 10 years, and Expanded Disability Status Scale (EDSS) score ≤5. Primary endpoints include relapses adjudicated by an independent panel and time to sustained accumulation of disability assessed by blinded evaluators. Results: 840 patients from 180 centers in 23 countries were randomized. Baseline characteristics (mean) were: age 35 years; disease duration 3.9 years; EDSS 2.7; with 1.6 and 2.7 relapses in 1 and 2 years prior to study entry, respectively. The most common prior MS therapies were interferon-beta (78.6%) or glatiramer acetate (32.5%); less than 5% of patients had received other prior MS therapy (some patients received more than one therapy). Conclusions: Database lock and study analysis will occur in late 2011. The principal efficacy and safety results will be presented. ®Rebif is a registered trademark of EMD Serono, Inc. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Twyman has received personal compensation for activities with Genzyme Corporation as a consultant, speaker and participant on advisory boards. Dr. Twyman has received research support from Genzyme Corporation. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Miller has received personal compensation for activities with Allergan, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Forest, Novartis, Sanofi Aventis, and Teva as a speaker. Dr. Miller has received research support from Allergan, Biogen Idec, Genzyme, Elan, Teva, Novartis, Ono, Sanofi Aventis, EMD Serono, and Roche-Genetech. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

Objective: Compare alemtuzumab and interferon beta-1a (IFNB-1a) on top-line clinical efficacy and safety outcomes in the phase 3 pivotal study: CARE-MS I. Background Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool. Design/Methods: CARE-MS I was a 2-year, randomized, rater-blinded, active-comparator, trial comparing alemtuzumab to IFNB-1a in active, treatment-naive relapsing-remitting MS (RRMS) patients. Alemtuzumab treatment was 12mg/day iv for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly for 24 months. Primary efficacy endpoints were relapse rate and time to 6-month sustained accumulation of disability (SAD). Results: 581 patients from 98 centers in 16 countries were randomized 2:1 to alemtuzumab or IFNB-1a. Mean age was 33; mean EDSS was 2; mean time since first episode was 2 years. Alemtuzumab reduced relapse rate by 55% compared to IFNB-1a (p Conclusions: Alemtuzumab significantly reduces the relapse rate in RRMS patients compared to an active comparator. Effect on disability accumulation was not significantly different, possibly due to the very low incidence of disability accumulation in the sample overall. The safety profile for alemtuzumab was consistent with previous studies. These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Brinar has nothing to disclose. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Stojanovic has nothing to disclose. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

Objective: Compare alemtuzumab and subcutaneous interferon beta-1a (IFNB-1a) on relapse outcomes from a phase 3 trial in patients with relapsing-remitting multiple sclerosis (RRMS). Background Over 2 years, alemtuzumab reduced the rate of relapse by 55% compared with IFNB-1a (p Design/Methods: CARE-MS I was a 2-year, randomized, rater-blinded, global trial comparing the efficacy and safety of alemtuzumab to subcutaneous IFNB-1a in active, treatment-naive RRMS patients. Alemtuzumab treatment was 12mg/day intravenously for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44mcg SC 3-times weekly for 24 months. Relapse rate was a co-primary endpoint. Relapse events were required to last at least 48 hours, required objective signs on exam as assessed by blinded raters, and were adjudicated by an independent relapse adjudication committee. Results: Annualized relapse rate was 0.18 (95% CI: 0.13, 0.23) for alemtuzumab-treated patients compared with 0.39 (95% CI: 0.29, 0.53) for IFNB-1a-treated patients (55% reduction, p Conclusions: Alemtuzumab significantly reduces relapses in RRMS patients compared with high-dose, high-frequency IFNB-1a. These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Brinar has nothing to disclose. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Stojanovic has nothing to disclose. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.