Of mice and men

HIV infection of the CNS probably occurs shortly after initial systemic infection, although in most individuals productive CNS infection develops only after immunosuppression. HIV-associated dementia (HAD) is a predominantly subcortical dementia that occurs in 15 to 20% of individuals with HIV infection. HAD is a chronic encephalitis with active HIV replication predominantly targeting macrophages and microglia. Macrophages are activated and evidence of immune activation correlates with the severity of neurologic disease. Despite the prevalence of HAD and the rapid pace of antiretroviral drug development leading to Food and Drug Administration (FDA) approval of 16 agents in the United States since 1987, only three placebo-controlled trials of antiretroviral therapy for HIV-associated cognitive impairment have been completed—two studying zidovudine monotherapy1,2 and the third and most recent, the addition of abacavir to standard antiretroviral regime.3 The relative dearth of controlled trials for HAD represents, in part, the successful validation of plasma viral load as an efficient and reliable surrogate marker of drug efficacy for systemic infection and the lack of such a surrogate marker for CNS infection. The FDA now approves new antiretrovirals on the basis of changes in plasma viral load. Mounting complex clinical trials where the outcome may be changes …