HIV-associated neurocognitive impairment (HNCI) is a significant burden to persons living with HIV infection, caregivers, and the healthcare system.

Although highly active antiretroviral therapy (HAART) has reduced the incidence of severe dementia and improves neurocognitive function in many, individual patient responses are quite variable, and the prevalence of HNCI remains high.

Thus the development of effective treatment strategies is of considerable public health importance.  Current consensus antiretroviral therapy (ART) guidelines provide no specific recommendations on the management of HNCI. Evidence from in vitro and in vivo experiments and uncontrolled human studies has failed to resolve controversy on whether antiretroviral (ARV) central nervous system (CNS) penetration and cerebrospinal fluid (CSF) virologic suppression are clinically important, and no randomized, controlled trials have compared the neurocognitive benefits of regimens with differing CNS penetration. The chemical profile of many ARVs currently in development suggests that their CNS penetration will be negligible.  Thus data on the importance of CNS penetration will become increasingly important as new agents are introduced into the clinical armamentarium.  In natural history studies, we have observed that among individuals with HNCI initiating new ART, those on more CNS penetrating regimens had greater CSF viral load (VL) reduction, and those who achieved CSF virologic suppression had better neurocognitive outcomes.

Together, these observations argue for a multi-center, randomized clinical trial to evaluate a CNS-targeted antiretroviral treatment strategy.  Such a trial would provide the level of evidence needed to formulate ART guidelines specific to HNCI.