Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder

Ronald J. Ellis, Scott Letendre, Florin Vaida, Richard Haubrich, Robert K. Heaton, Ned Sacktor, David B. Clifford, Brookie M. Best, Susanne May, Anya Umlauf, Mariana Cherner, Chelsea Sanders, Craig Ballard, David M. Simpson, Cheryl Jay, J. Allen McCutchan

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89 Scopus citations


Background. Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection. Methods. This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non-CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16. Results. The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intentto- treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), andmedian nadir and current CD4+ T-cell counts of 175 cells/μL and 242 cells/μL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], -31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, -.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T. Conclusions. This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded.

Original languageEnglish
Pages (from-to)1015-1022
Number of pages8
JournalClinical Infectious Diseases
Issue number7
StatePublished - 2014


  • AIDS
  • Antiretroviral therapy
  • Cognitive disorders/dementia
  • HIV


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