Neurocognitive Disorders: New Developments and Therapies
A Randomized, Controlled Trial of a Central Nervous System-targeted ART STrategy for HIV-associated Neurocognitive Disorders
Ronald Ellis, MD, PhD
20th Conference on Retroviruses and Opportunistic Infections (CROI, February 2013)
Ellis R, Vaida F, Letendre S, Haubrich R, Heaton RK, McCutchan JA, Cherner M, Umlauf A, Sacktor N, Clifford DB
Background: Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into CNS tissues, potentially influencing their effectiveness in treating brain infection and neurocognitive disorders.
Methods: This randomized, controlled, open-label clinical trial evaluated the utility of a CNS-targeted (CNS-T) ARV strategy versus non-CNS-targeted therapy for patients with HIV-associated neurocognitive disorders (HAND) initiating or changing an ART regimen. The design called for 120 patients at 5 study sites to be randomized 1:1 to the study arms. Baseline clinical factors such as ARV experience were balanced across arms using an adaptive approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16, adjusted for initial performance.
Results: Of 326 screened participants, 59 met entry criteria and agreed to participate. The most frequent reasons for non-enrollment were absence of HAND, inability to contact and patient/provider decision to accelerate or forego changes in ART. In December 2011, the study's Data Safety and Monitoring Board recommended terminating the trial based on a low likelihood of detecting a difference in the primary outcome and slow accrual. No safety concerns were identified. The primary intent-to-treat analysis was done on 49 subjects with week 16 outcome data: 39 men, 10 women, mean age 44 (+/-8), median nadir and current CD4 175 and 242. The proportional reduction (improvement) in GDS from baseline was non-significantly larger (7%; 95% CI [-31%, 62%]) in the CNS-T versus non-CNS-T arm, representing a treatment effect size (ES) of 0.087 (95% CI, -0.475, 0.648). A pre-specified secondary analysis showed an interaction between baseline plasma virologic suppression and treatment, driven by the subgroup with suppression on ART, in which the mean improvement for CNS-T (N=7) versus non-CNS-T (N=6) corresponded to a large standardized ES = 1.25 (95% CI 0.628, 1.858).
Conclusions: This study found no overall difference in neurocognitive benefit for a CNS-targeted ARV strategy. The results argue against a large effect of ARV CNS penetration on neurocognitive improvement, though a small beneficial effect cannot be excluded, as the study was not designed to evaluate non-inferiority, accrual was incomplete, and a secondary analysis was consistent with superiority of CNS-T in a subgroup.