HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment.

The advent of combined active antiretroviral therapy (cART) dramatically improved HIV management and patient care of HIV-infected individuals. This treatment regimen resulted in a significant reduction of HIV/AIDS-related mortality and greatly improved life expectancies of those patients with access to cART. However, among many HIV-related complications, neurocognitive dysfunction, known as HIV-associated neurocognitive disorder (HAND) has been a major issue. While the cART regimen has been effective in reduction of HAND in many patients, the prevalence of HAND is increasing as HIV/AIDS patients live longer. HIV infection and its subsequent manifestation of HAND is complex. It is evident that the brain can serve as a sanctuary for HIV replication and HAND can remain in patients even with cART treatment due to poor blood-brain barrier permeability of the majority of current antiretroviral agents. Conceivably, cART needs to have improved CNS penetration properties for effective treatment and possible prevention of HAND. Therefore, design and development of new antiretroviral agents that can penetrate into the CNS effectively, could block HIV replication and significantly reduce the viral load in cerebrospinal fluid. This may prevent HAND and related symptoms. HIV protease inhibitors (PIs) are a critical component of cART. Over the years, we have designed and synthesized a range of highly potent and novel PIs including the FDA approved drug, darunavir, which is used as a first-line treatment. In an effort to improve CNS penetration, we have been involved in the design and development of potent PIs with improved