Background: The effectiveness of combination antiretroviral therapy (ART) in the central nervous system (CNS) remains theoretically problematic because of restricted drug penetration. We have initiated a longitudinal study to examine this issue using CSF as a CNS window.

Methods: This Sentinel Neurological Cohort (SNC) is a prospective longitudinal study of HIV-infected subjects assigned to 3 groups based on entry treatment status and plasma HIV RNA values: Group 1 (successes)—taking ART with plasma viral loads (VL) < 500 copies/mL; Group 2 (failures)—on ART with plasma VL ≥ 500 copies; and Group 3 (no ART)—off therapy, either naïve or no treatment within 3 months. We now report findings on the first 90 participants at study entry. As a control, 32 HIV negative subjects were similarly studied cross-sectionally. Group differences were analyzed by ANOVA and SNK post-hoc test with alpha = 0.01.

Results: Some salient findings (expressed as mean ±SD) are shown in the table below.

 

As expected by entry criteria, the median plasma HIV RNA concentration (Roche PCR, setting 19 copies/mL as “floor” value) in Group 1 differed from Groups 2 and 3 which were nearly equal (NS). By contrast, both the CSF viral loads and the log₁₀ differences between plasma and CSF VLs (Δ[P-C]) differed significantly between all 3 groups. Most notably, the CSF VL in the failure group was about 10-fold lower than in the off-ART group despite the nearly equal plasma values—hence also showing a 10-fold wider Δ(P-C) in the failures than untreated subjects. While the CSF white blood cell counts (WBC) were significantly higher in the off-ART group, both treated groups showed normal counts. CSF neopterin, a marker of local macrophage activation, measured in a subset of subjects showed increasing mean levels in Groups 1, 2, and 3, with Groups 2 and 3 differing significantly from normal but not each other, while Group 3 also differed from the successes.

Conclusions: ART has a beneficial effect on CSF HIV infection both in those with plasma viral suppression (in whom CSF suppression is similar) but also in those for whom treatment is unsuccessful in completely suppressing plasma HIV (in whom CSF treatment effect is proportionally greater). ART also reduces CSF WBC responses and macrophage activation. Whether these effects relate to intracellular actions of certain drugs within the CNS or to other mechanisms remains to be established.