The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

The present study examined neuropsychological (NP) functioning and associated medical, neurological, brain magnetic resonance imaging (MRI), and psychiatric findings in 389 nondemented males infected with Human Immunodeficiency Virus-Type 1 (HIV-1), and in 111 uninfected controls. Using a comprehensive NP test battery, we found increased rates of impairment at each successive stage of HIV infection. HIV-related NP impairment was generally mild, especially in the medically asymptomatic stage of infection, and most often affected attention, speed of information processing, and learning efficiency; this pattern is consistent with earliest involvement of subcortical or frontostriatal brain systems. NP impairment could not be explained on the bases of mood disturbance, recreational drug or alcohol use, or constitutional symptoms; by contrast, impairment in HIV-infected subjects was related to central brain atrophy on MRI, as well as to evidence of cellular immune activation and neurological abnormalities linked to the central nervous system. (JINS, 1995, 1, 231–251.)

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NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.