Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control.

BACKGROUND: Despite the efficacy of highly active antiretroviral treatment (HAART), a large proportion of human immunodeficiency virus (HIV)-infected patients may develop moderate neurocognitive impairment. Antiretroviral drug passage into the central nervous system may be relevant for preventing and treating HIV-associated neurocognitive disorder; nevertheless, clear cerebrospinal fluid (CSF) pharmacodynamic targets are not known. METHODS: HAART-treated adults with wild-type HIV were prospectively enrolled. CSF concentrations (measured by mass spectrophotometric methods) and inhibitory quotients (CSF concentrations divided by in vitro 50% and 95% inhibitory concentrations) were compared among different drugs and related to CSF HIV RNA levels. CSF escape was defined as CSF HIV RNA >50 copies/mL despite contemporary plasma HIV RNA below that threshold. RESULTS: One hundred twenty-seven patients (91 male [71.7%], 93 white [73.2%], with a median age of 46 years [interquartile range, 40.5-54.5 years]) provided 174 paired CSF and plasma samples. Twice-daily darunavir, once-daily darunavir, and efavirenz had the highest CSF 95% inhibitory quotients (18.5, 8.2, and 6.4, respectively). Higher nadir CD4 cell count (P = .01) and plasma HIV RNA <50 copies/mL (P < .001) were independent predictors of controlled CSF HIV RNA. Optimal drug exposure (CSF detectable drugs and 95% inhibitory quotient >1) was protective for CSF escape (P = .01). CONCLUSIONS: Cerebrospinal fluid 95% inhibitory quotients may be used to compare antiretroviral drug compartmental exposure; they deserve longitudinal studies to assess the adequacy of CSF drug concentrations in treated HIV-infected patients.

Cerebrospinal fluid biomarkers in patients with plasma HIV RNA below 20 copies/mL.

INTRODUCTION: Low level HIV-1 CSF replication (CsfLLV) is often found even in patients with controlled plasma viraemia. The clinical consequences of such finding are uncertain; however, both symptomatic neurological disturbances and neurocognitive disorders may arise in the context of CSF-escape. Two reports suggested that low level replication in the CSF may be associated with increased CSF neopterine although the impact on other markers of neuroinflammation/damage is currently unknown. MATERIALS AND METHODS: Patients with neurocognitive disorders, new neurological symptoms or followed in longitudinal studies were included provided that they were on HAART, with last available viral load below 20 copies/mL and without central nervous system (CNS)-involving infections/neoplasms. After brain Magnetic Resonance (MR) CSF HIV RNA (CAP/CTM HIV-1 v2.0) and biomarkers [total tau (t-tau), phosphorylated tau (p-tau), 1-42 Beta amyloid (Beta42), neopterine and S100beta] were measured through validated methods. Data are presented as medians (IQR); non-parametric tests are used for all analysis. RESULTS: 70 patients [66.7% male, median age 47.8 years (40-56), median BMI 22.2 kg/m2 (20-24)] were enrolled. Current and nadir CD4+ cell count were 379 (219-656) and 116 cell/mm3 (46-225); HIV RNA was undetectable since 19.7 months (9-53). CSF HIV RNA was undetectable in 24 (34.3%), below 20 copies/mL in 26 (37.1%), above 20 copies/mL in 25 patients [35.7%, median 69 copies/mL (41-134]). Median (IQR) CSF biomarkers values were as follows: t-tau 109 pg/mL (<75-161), p-tau 31.6 pg/mL (23.4-35.4), Beta42 818 pg/mL (623-973), neopterine 0.58 ng/mL (0.45-0.87) and S100beta 149 pg/mL (110-186). Patients with CsfLLV did not show significant differences as for demographic, therapeutic, virological, radiological variables. t-tau (134 vs 92.6, p=0.05) and Beta42 (953 vs 675, p=0.007) were higher in patients with CsfLLV. Neopterine levels were directly associated with p-tau (rho=0.42, p=0.01), with CSF HIV RNA (rho=0.24, p=0.06). and inversely with current CD4 cell count (rho=-0.29, p=03). CONCLUSIONS: In patients with controlled HIV viraemia (below 20 copies/mL), CSF total tau, Beta42 and neopterine were higher in patients with detectable HIV RNA. Prospective and adequately powered studies are warranted for evaluating the clinical significance of compartmental viral replication and immune activation.