Is treated HIV infection still toxic to the brain?

Clinically apparent HIV infection, accompanied by CNS opportunistic infections and HIV encephalopathy, was often associated with profound structural and functional brain effects prior to the introduction of anti-retroviral therapy (ART). With treatment, HIV structural and functional brain effects are smaller and have not been as easily detected. With near complete elimination of CNS opportunistic infections, the HIV neuroimaging research community now grapples with the problem of detecting subtler structural and functional changes against a background of persisting confounds, such as comorbidities and clinical features common in the HIV infected population. This situation also raises the question of whether imaging measure changes that are reported as HIV brain effects are purely related to viral infection, rather than originating from confounding effects that might include age, substance use, hepatitis C coinfection, cerebrovascular risk factors, ART, premorbid cognitive skills and illness duration. In addition to cohort characteristics, variation in image acquisition and analysis techniques may also contribute to study outcome heterogeneity. We review the potential effects of these confounds on detection of HIV infection effects and discuss strategies to avoid or mitigate the effects of these confounds. We then present a systematic approach to measurement, design and analysis in HIV neuroimaging studies, combining both experimental and statistical control techniques to determine if HIV infection effects persist, fluctuate or worsen in groups achieving viral suppression from ART.