Has HIV-associated neurocognitive disorders now transformed into vascular cognitive impairment?

The article by Su et al.[1] raises some important points in relation to HIV-associated neurocognitive disorders (HAND) in the combination antiretroviral therapy (cART) era. Since the introduction of cART, there has been a decline in the incidence of HAND but not the prevalence. Further, the more severe forms of HAND are now virtually confined to cART-naïve patients or those with multidrug-resistant HIV. Yet milder forms of HAND remain and although mild they are still functionally significant, impacting upon ability to work and perhaps most fundamentally upon cART adherence. Thus, there appears to be a therapeutic paradox: very potent drugs have essentially eliminated severe HAND but not mild HAND; one would have predicted that mild HAND would be an easier target for elimination by cART as opposed to severe HAND but the opposite is true. Why should this be? Several explanations have been advanced [2] but none has been definitively proven at a population level. As noted by Su et al.[1], HIV-infected patients are at an increased risk of developing vascular disease for several reasons. Vascular disease appears to be accelerated in HIV-infected individuals [3] and so some of these individuals may develop vascular cognitive impairment. Indeed, vascular risk factors are now emerging as being more important than more classical factors for HAND [4] and the core neuropsychological profile of vascular cognitive impairment overlaps with that of HAND. The rate of stroke is certainly increased in HIV [5], though at present the rate remains relatively low. Nonetheless, the role of small vessel disease independent of stroke causing vascular cognitive impairment mimicking or amplifying HAND has not been explored yet remains a significant possibility. In the study by Su et al.[1], the significance of white matter hyperintensities (WMH) as seen on MRI brain scans is advanced as well as their relevance to HAND. The advantages of the study are its prospective design, the inclusion of patients with sustained aviraemia (below 40 cpml or occasional viremia below 200 cpml) and without severe immune compromise, the blinded MRI assessment, and an appropriate control group. The disadvantages are that by design the study did not include women. They concluded that HIV-infected men had more extensive periventricular, but not deep WMH, and that the presence of HAND was associated with both types of lesions. However, the association was mediated by measures of verbal fluency and attentional processing. Further, WMH were related to older age, higher diastolic blood pressure, D-dimer levels, and time spent with a CD4 cell count below 500/μl. Somewhat surprisingly, there was no relationship to particular classes of cART. These results support earlier treatment in the course of HIV disease along with optimization of cardiovascular risk factor reduction. Are the conclusions true? The result that current cART era HAND is now related to vascular cognitive impairment is by inference. In the non HIV population, WMH are related to cerebral small vessel disease which in turn is related to vascular cognitive impairment. Nonetheless, the rigour of the study does suggest such a conclusion albeit tentatively. The results are in accord with other studies of HAND in the cART era [4]. However, if HAND is now essentially vascular cognitive impairment why is there evidence, checkered as it is, for the efficacy of so-called neuro-cART [6]? Why would cART intensification with maraviroc appear to improve HAND in aviraemic patients [7]? Perhaps, there are two explanations: HAND is now mixed in its cause in some cases driven by vascular disease and in others by HIV. Both explanations may be correct though with HIV acting directly and indirectly to cause HAND: a potential unifying explanation is that HAND in the cART era is driven by the production of HIV components such as Tat and Nef because of the inability of current cART regimens to affect immediate transcription after integration [8,9]. These products are not only neurotoxic in their own right but are also vasotoxic and immunogenic, thereby causing vascular damage [3,4]. Is HAND now really vascular cognitive impairment in disguise? Although, the data from Su et al.[1] add to the mounting evidence that vascular disease is a significant factor in cART era HAND, the importance of other factors such as substance abuse, diabetes [10], and possibly accelerated ageing should not be forgotten. A more definite answer as to the relative contributions of these factors at a population level, however, will only come from further large well designed studies, supported by neuropathological analyses. Acknowledgements Conflicts of interest There are no conflicts of interest.