Soon after the introduction of protease inhibitors and the widespread use of combination antiretroviral therapy, the concept of eradication of HIV-1 from infected individuals seemed a realistic goal.¹ However, the possibility that sanctuaries for virus existed within anatomical sites, such as the central nervous system (CNS), that are protected from the peripheral immune response and that may have impaired drug penetration loomed as a major barrier to eradication. Today we are more cautious about the prospect of HIV-1 eradication. Yet consideration of protected viral reservoirs remains important, particularly in light of data that show different antiretroviral resistance mutations in viruses from brain compared with peripheral sites of infection.² Could the HIV epidemic be transformed into one in which systemic infection is controlled but brain infection, and dementia, persist? Could protected sites theoretically reinfect the blood and cause treatment failure, especially if they fostered local outgrowth of drug resistant virus? Many antiretrovirals, particularly the protease inhibitors, yield limited brain and cerebrospinal fluid (CSF) drug concentrations.³ Are we thus allowing increased viral replication in the brain and potential treatment failure in our patients? To assess the importance of brain penetration of anti-HIV agents, several issues and questions must first be addressed. We conclude that until these issues are resolved antiretroviral regimens should be designed to include agents with good CNS penetration.

AIDS dementia is estimated to occur in about 15% of HIV-1 infected patients with advanced disease. The disorder is uncommon in the absence of significant immunosuppression and patients typically have peripheral blood CD4 cell counts below 200 ×10⁶/l. The pathogenesis of AIDS dementia is incompletely understood, but is intimately linked to productive viral infection of brain macrophages or microglia; secondary mechanisms related to host factors as well as viral components probably play an important part.⁴ …