The brain and HAART: collaborative and combative connections

To summarize contemporary observations regarding the effects of highly active antiretroviral therapy (HAART) on the brain.

The effects of HAART on the structure and function of the brain during HIV/AIDS is currently a subject of intense interest because the brain is one of the most drug-impenetrable organs that is infected by HIV-1 and as such represents an important reservoir for replication-competent virus. The effects of HAART on neurocognitive impairment caused by HIV-1 infection remain uncertain with both beneficial and adverse outcomes reported with different HAART regimens. Similarly, the effects of individual HAART regimens on viral quantity in cerebrospinal fluid as a surrogate indicator of brain virus burden are variable. Indeed, the situation is further complicated by the ranking of antiretroviral therapies (ARTs) by their central nervous system penetration-effectiveness score on the basis of ART concentrations in cerebrospinal fluid. Experimental studies have also yielded equivocal findings depending on the model and individual ART. At the same time, a burgeoning body of experimental data has demonstrated neurotoxic effects of several ARTs, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

HAART selection strategies are currently guided by efficacy, resistance testing, toxicity, potential drug interactions and theoretical brain penetration. As improved strategies are developed to target the viral reservoir within the brain, greater knowledge of the effects of ARTs on neural tissues will be needed to operationalize their use in a rational manner that maximizes antiretroviral efficacy and minimizes the neurotoxic complications.