Researchers from the CHARTER study found that nadir CD4 count is strongly associated with neurocognitive impairment (NCI) even after adjusting for confounding variables that can influence both nadir CD4 and NCI. This association is attenuated with combination antiretroviral therapy (CART) use, but remains present when examining only those on CART with an undetectable viral load. These findings suggest that low nadir CD4 could represent a “legacy event” in HIV infection that establishes slow or non-reversible brain damage. Prevention of severe immunosuppression may lead to more favorable neurocognitive outcomes.