Despite optimal responses to combination antiretroviral therapy (cART), HIV-infected children continue to show neurocognitive deficits with macro- and microstructural brain injury and signs of neuroinflammation. Subtherapeutic central nervous system (CNS) drug levels may contribute to neuropathology in these children. Also, chronic HIV infection has been associated with blood-brain barrier (BBB) breakdown. Pediatric data on cerebrospinal fluid (CSF) cART penetration is scarce. We evaluated cART levels in CSF and plasma and assessed whether CSF drug penetration is related to BBB function, intrathecal inflammation and immune activation in HIV-infected children on suppressive cART.
This cross-sectional study included perinatally HIV-infected children between 8-18 years old from the Academic Medical Center, Amsterdam. CSF was collected from a subset of patients stable on cART in whom a lumbar puncture was indicated as part of routine patient care. CSF and plasma total drug levels were measured and CSF penetration was assessed using each drug’s CSF-to-plasma concentration ratio. BBB permeability was defined as the albumin CSF-to-plasma ratio. Intrathecal inflammation/immune activation markers included CRP, IL-6, soluble CD14 and soluble CD163. Potential associations were explored using Spearman’s rank correlation.
Of the 36 perinatally HIV-infected children included, paired CSF and serum samples were available from 20 cART-treated children. All participants were virologically suppressed in blood and CSF. The median CSF penetration of lopinavir (0.12%), efavirenz (0.36%) and tenofovir (1.95%) was poor compared to lamivudine (34%), emtricitabine (35%), nevirapine (48%), zidovudine (52%) and abacavir (56%) (Figure 1). CSF penetration of lamivudine, abacavir, efavirenz and lopinavir was not associated with age or BBB permeability. There was no correlation between CSF penetration of these antiretrovirals and inflammation/immune activation markers soluble CD14, soluble CD163, CRP and IL6 in CSF.
Similar to adult patients, CSF penetration of lopinavir, efavirenz and tenofovir is poor in pediatric HIV. We found no associations between CSF penetration of cART and BBB permeability or inflammatory markers in CSF. This suggests cART-specific properties may be more important in CSF penetration than the studied host related factors. Alternatively, HIV related neuroinflammation in children might be at such a low grade, that BBB permeability remains unaltered.