In the era of
highly active antiretroviral therapy (
HAART), HIV-1-associated
neurocognitive disorder (HAND) continues to be a common and significant morbidity among individuals infected with HIV. The term HAND encompasses a spectrum of progressively severe CNS involvement, ranging from asymptomatic neurocognitive impairment and minor
neurocognitive disorder through to the most severe form of HIV-associated
dementia (HAD). While the incidence of HAD has declined significantly with
HAART, the milder forms of HAND persist. In addition, HAND now develops in individuals with less advanced immunosuppression. The reasons for the persistence of milder forms of HAND in individuals treated with
HAART are not entirely known. There are several hypotheses to explain this phenomenon that include the legacy effect, a failure of
antiretroviral agents to reverse neurological damage, poor access of
antiretroviral agents to the CNS, chronic systemic immune activation associated with microbial translocation products, sustained CNS
inflammation, the improved survival of HIV-seropositive individuals and the possible contribution from aging,
amyloid deposition and other co-morbidities. In contrast, the incidence of HIV-associated CNS opportunistic processes including
progressive multifocal leukoencephalopathy,
tuberculosis, CNS
toxoplasmosis, cytomegalovirus
encephalitis,
cryptococcosis and primary CNS
lymphoma has declined dramatically with the introduction of
HAART. This review briefly summarizes our current understanding of HAND and the pathological mechanisms involved, namely direct injury from HIV-1 and
viral proteins, indirect neurotoxicity from proinflammatory
cytokines and chronic, sustained immune activation in the CNS. To date, only
HAART has been shown to benefit HAND despite numerous controlled trials of adjunctive '
anti-inflammatory' agents. Although
HAART has a profound impact on the incidence and severity of HAND, there exists a 'therapeutic gap' as even
HAART that is effective at inducing durable virological suppression may only partially reverse HAND. In addition, there may be potential CNS adverse effects of
antiretroviral agents. There is an ongoing multicentre clinical trial to investigate the role of the CNS Penetration-Effectiveness index, an
indicator of drug permeability and availability in the CNS, to help guide the choice of
antiretroviral agents in the treatment of HAND. With recent recommendations for earlier treatment intervention with
HAART for HIV-1
infection, it remains to be seen the effects of this on HAND. There is an urgent need to better define the therapeutic guidelines for the prevention and treatment of HAND.