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A Randomized, Controlled Trial of a CNS-Targeted Antiretroviral Therapy (ART) Strategy for HIV-Associated Neurocognitive Disorders
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Reported by Jules Levin
CROI 2013
Ronald J. Ellis
S. Letendre, F. Vaida, R. Haubrich, R.K. Heaton, N. Sacktor, D.B. Clifford, B.M. Best, S. May, A. Umlauf, M. Cherner, C. Sanders, C. Ballard, D.M. Simpson, C. Jay, J.A. McCutchan
Link to webcast:
http://webcasts.retroconference.org/console/player/19408?mediaType=podiumVideo
from Jules: my impression, the researchers on this study & who have over the years believed in CPE (CNS Penetration Effectiveness Score), are not convinced this study dispels their continuing belief that CNS targeted with a higher CPE score can in fact be beneficial to at least some patients with neurocognitive problems. this study did not meet enrollment thresholds, it had trouble enrolling, study accrual was not meeting the goals, they were "significantly off accrual targets", so DSMB recommended study be terminated although the "futility boundary was not met", "59 of the planned 120 subjects were randomized and accounting for loss to followup which was not different between the 2 arms the final ITT analysis was based on 49 subjects who provided the week 16 data". In the Q&A after the presentation Bruce Brew went to the mic and raised 2 I think important questions: the patients subjective evaluation of neurocognitive symptoms they were or were not experiencing and suggesting that 16 weeks may be too short to observe benefits, that 40 weeks would be preferable, raising the point that it is very difficult I think to conduct a study to evaluate this question, whether a CPE enhanced regimen can benefit a patient with neurocognitive deficits, there are so many complexities involved.....see back-up slides at bottom of report after cknowledgements.
Ellis: "the first public summary of a clinical trial that was designed to answer the question of whether HIV-associated neurocognitive disorders might benefit from CNS targeted antiretroviral therapy"
"This study was based on the theoretical rationale that achieving better distribution of antiretroviral drugs into the CNS would reduce CNS viral replication and several important downstream mediators of neuronal dysfunction, thereby maximizing neurocognitive improvement with ART. This rationale was buttressed by observational reports supporting the benefits of CNS-targeted ART (CNS-T), also known as "neuroHAART", and by expert opinion as reflected in published treatment guidelines."
Ellis: "In summary, the interim analysis of this randomized clinical strategy trial showed virally suppressive CART to be associated with modest overall improvement in neurocognitive performance over 16 weeks, particularly among the ARV-naïve patients. CNS-T was not superior to non-CNS-T. While virologic responses in this study of neurocognitively impaired individuals was significant for both arms, suppression rates were suboptimal by comparison to historical studies of (mostly) non-impaired individuals, and suppression rates were non-significantly reduced in the CNS-T arm. The clinical significance of this reduced virologic suppression rate was mitigated by differences between the arms in factors known to influence virologic suppression: namely lower CD4 nadirs and higher rates of hepatitis C coinfection in the CNS-T arm. CNS-T was not shown to be superior in CSF virologic suppression - a finding that differs from several recently published, larger observational reports. In a secondary analysis, an interaction between virologic suppression in plasma and study treatment was observed. Among pts virolgically suppressed at study entry, CNS-T was associated with superior neurocognitive improvement. The robustness of this finding was limited by small numbers and confounding with age, as virologically suppressed pts tended to be older and modeling age removed the significance of study arm in this analysis. "
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