For subjects with higher CD4 lymphocyte counts, the ongoing START study will prospectively assess NC function in HIV-positive subjects commencing ART at an earlier stage of HIV disease. Therefore, ART is recommended buy MDV3100 in NC symptomatic subjects whose CD4 lymphocyte count itself is an indication to commence therapy. In the absence of scientific data, in cognitively symptomatic subjects with higher CD4 lymphocyte counts in whom ART would not be otherwise indicated, a recommendation to consider commencing ART is based (i) on observed improvements in cognitive function

reported in subjects with lower CD4 lymphocyte counts commencing therapy [114], and (ii) to avoid a future decline in CD4 lymphocyte count in such subjects, given the well-described association between low nadir CD4 lymphocyte count and NC impairment [112]. Suboptimal adherence to therapy may occur more frequently in subjects with NC impairment, hence find more adequate support services to optimize adherence

are essential. We recommend patients with HIV-associated NC disorders start standard combination ART regimens (1C). Proportion of patients with HIV-associated NC disorders on ART containing two NRTIs and one of an NNRTI, a PI/r or an INI. Although during the earlier years of ART, clear benefits on cerebral function of individual ARV drugs such as ZDV were reported [117] and the benefits of combination therapy overall are well described [114], data are sparse regarding any differences in these benefits between individual agents or combinations. Within cohort

studies, the use of the NRTI class within ARV regimens has been associated with a reduced risk of severe HIV-associated dementia [118] compared with the use of other regimens; however, the confounders of a cohort study limit interpretation of these data. Recently, attempts have been made to establish a relationship between cognitive function and CNS ARV drug delivery based on an ARV scoring system known as the clinical penetration effectiveness (CPE) score [119]. The Tacrolimus (FK506) CPE score aims to rationally score the cerebral effects of individual ARV agents. However, the system is predominantly designed around pharmacokinetic modelling rather than pharmacodynamic endpoints such as data describing changes in NC function. Studies that have assessed the correlation between the CPE scores of ARV regimens with NC function report conflicting findings with some cohorts reporting a positive association [120, 121], and others describing a negative association [122]. Given the potential flaws outlined in the design of the CPE score, a lack of prospective clinical data and discrepancies in findings within cohort studies, the CPE score should not influence therapeutic decisions in subjects with NC impairment commencing ART.