Cerebrospinal fluid (CSF) viral escape occurs in 4-20% HIV-infected adults on antiretroviral therapy (ART), yet the impact of ART regimens on CSF escape in HIV infection is unclear.
Prospective study of 1063 participants on ART from the NNTC, CHARTER, and HNRC cohorts (age ≥18, baseline plasma viral load (VL) ≤400 copies/ml between 2005-2016). CSF escape was defined as paired CSF VL ≥ plasma VL, or CSF VL >50 copies if plasma VL was undetectable. Odds ratio for ART regimens (PI with nucleoside reverse transcriptase inhibitor [PI+NRTI] versus other ART [excluding monotherapy]) and CSF escape was estimated using mixed-effects models, adjusting for age at HIV diagnosis, duration of infection, CD4 nadir, plasma VL≤50 copies/mL, and number of CSF exams. Drug resistance mutation frequencies in plasma and CSF were calculated using a merged dataset from cohort participants and published studies (n=99).
Baseline mean age was 46 years; median plasma VL, CD4 nadir, and CD4 count was 50 copies/mL, 88 cells/μL, and 424 cells/μL, respectively. Forty-eight percent were on PI+NRTI, 33% on non-NRTI, and 6% on integrase inhibitors. During 4,785 total person-years of follow up, CSF escape occurred in 77 participants (7.2%, n=127 events). PI+NRTI use was an independent predictor of CSF escape (OR 3.1 [95% CI: 1.8-5.0]) in adjusted analyses and models restricted to plasma VL ≤50 copies/ml (p<0.001). Regimens containing atazanavir (ATV) were a stronger predictor of CSF viral escape [OR 3.2 [95% CI: 1.8-5.5]) than non-ATV PI+NRTI regimens [OR 2.7 [95% CI: 1.5-4.8]) when compared to other ART regimens. Plasma and CSF M184V/I along with thymidine-analog mutations (TAMs) were more frequent in CSF escape compared to those without escape (23% vs. 2.3%), while accessory resistance mutation frequencies were similar. CNS penetration-effectiveness (CPE), genotypic susceptibility scores (GSS), and GSS-adjusted CPE scores were calculated for CSF escape patients with M184V/I mutations (n=34). The median unadjusted CPE score was 7 [IQR: 7-8], but adjusted CPE scores were low (<5) for CSF and plasma in 27 (79%) and 13 (38%) patients, respectively, indicating suboptimal CNS drug availability.
PI+NRTI regimens, in particular ATV-containing regimens, are independent predictors of CSF escape in HIV+ patients. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations. These findings suggest optimizing ART regimens may reduce risk of asymptomatic CSF escape.