Evidence-based treatment for HIV-associated dementia and cognitive impairment: why so little?

The Abacavir Trial in Context HIV-associated dementia (HAD) and milder forms of cognitive impairment produce a spectrum of disability that ranges from complete inability to care for oneself to reduced work efficiency and quality of life. HAD is believed to arise from a confluence of adverse effects on neuronal function resulting both from HIV itself and from disturbances in cellular signalling, particularly in the immune system, that further damage neurons. More than two decades after the recognition of HAD as a clinical entity, guidelines for antiretroviral drug treatment in people with HAD and cognitive impairment have yet to be established. The study reported in PLoS Clinical Trials by Brew et al. [1] was designed to help develop such guidelines by testing whether adding a single ‘‘neuroactive’’ antiretroviral, abacavir, to an existing regimen would benefit brain function in patients with dementia. Abacavir is a potent inhibitor of HIV reverse transcriptase that interferes with the viral lifecycle and shows reasonably good penetration into central nervous system (CNS) tissues. The trial was historically important because it was done at a pivotal time in the development of antiretroviral therapy, as potent combination drug regimens including protease inhibitors emerged into widespread use in the United States, Europe, and Australia. The rationale for the study was simple and transparent. It was anticipated that this ‘‘CNS active’’ agent would suppress a potential reservoir of HIV in the central nervous system, where other drugs, especially protease inhibitors, might not be effective. At the time this study was designed, a number of important scientific observations about HAD and its treatment had been made. Zidovudine, the earliest available nucleoside reverse transcriptase inhibitor, seemed to improve the motor functions of people with HAD when given in higher doses than normally used for treatment of systemic HIV disease [2]. Additionally, observational data showed that dementia prevalence in the West dropped after zidovudine became available, suggesting that zidovudine prevented HAD [3,4]. Even so, the burden of mild cognitive impairment in HIV remained substantial [5–7].