Publication Abstract Display | Type: Poster | Title: Impact of ART regimens on CSF viral escape in HIV-1 infected adults. | Authors: Mukerji S, Misra I, Lorenz D, Uno H, Morgello S, Franklin D, Ellis R, Letendre S, Gabuzda D | Date: 03-04-2018 | Abstract:CSF viral escape occurs in 4-20% of ART-treated HIV-1 infected adults, yet the impact of ART regimens on CSF escape in virologically controlled HIV infection is unclear.
This is a prospective multicohort study of 1063 participants from the National NeuroAIDS Tissue Consortium, CNS HIV Antiretroviral Therapy Effects Research Study, and HIV Neurobehavioral Research Center on ART (baseline age ≥18, plasma viral load (VL) ≤400 copies/ml, ≥1 visit with CSF VL between 2005-2016) followed until 2 consecutive plasma VL >1000 copies/ml or last visit. 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 (protease-inhibitor 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 HIV infection, CD4 nadir, plasma suppression (≤50 copies/mL), number of CSF exams, and cohort. 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 (SD 8.9); 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-nucleoside reverse-transcriptase inhibitors, 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, ≥2 events in 36% of the 77). PI+NRTI use was an independent predictor of CSF escape (OR 3.1 [95% CI: 1.8-5.1]) in adjusted analyses; the association remained significant when plasma VL was restricted to ≤50 copies/ml (p<0.001). Other factors associated with CSF escape were younger age at diagnosis, unsuppressed plasma VL, and low CD4 nadir. Plasma and CSF M184V/I combined with thymidine-analog mutations (TAMs) were more frequent in CSF escape compared to those without escape (23% vs. 2.3%), while frequency of accessory resistance mutations was 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%) of these patients, respectively.
These results identify PI+NRTI regimens as independent predictors of asymptomatic CSF escape in treated HIV+ patients after accounting for other known risk factors. Furthermore, reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations on multi-drug ART regimens. Given that M184V/I and TAM mutations and suboptimal drug levels in the CNS can predispose to CSF viremia, optimizing ART regimens is critical to reduce the risk of CSF escape. |
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