CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

years, and 15% at 6 years. Baseline plasma HIV RNA correlated with baseline NPZ-4 (p=0.005, adjusted β=-0.103, 95% CI -0.176 to -0.031). GBTA revealed significant improvement in cognitive test performance in all participants from baseline to year 2, and from year 2 to year 6 (all p<0.001). In addition, the time effect analysis showed that individuals’ NP performance significantly changed overtime (F(32,2) ≥21.36, p<0.001). The average degree of improvement (∆z- score=1.22) exceeded that estimated from practice effects alone. In addition, the average degree of improvement was more pronounced for individuals who had z-score <-1 at baseline (∆z-score=2.61). Conclusion: Our findings reveal favorable long-term cognitive performance in the context of ART-induced viral suppression initiated during early infection. Improvement occurs in the cohort over the course of treatment and exceeds that expected from practice effect. The results suggest the need of proactive identification and health care system readiness for this unique group of patients.

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. Conclusion: 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.

Oral Abstracts

124 SIV REBOUND IN THE SPINAL CORD AFTER STOPPING ART: A NOVEL CNS RESERVOIR Megan E. McCarron, Lisa Mangus, Samuel A. Brill, Sarah E. Beck, Kelly A. Metcalf

Pate, Suzanne E. Queen, Joseph Mankowski Johns Hopkins University, Baltimore, MD, USA

Background: Growing evidence implicates the brain as a long-term latent HIV reservoir. The spinal cord, like the brain, contains HIV-infected microglia, but has not been evaluated as a potential HIV reservoir. This SIV/macaque study compared brain versus spinal cord by quantitating SIV DNA after long-term ART suppression, and by measuring SIV RNA tissue levels after release from ART to test if the spinal cord serves as a source of rebound virus. Methods: 10 SIV-infected pigtailed macaques were treated with PMPA, FTC, and dolutegravir for 4 months. Plasma and CSF SIV RNA became undetectable within 40 days of starting ART. 4 of the 10 SIV-infected treated animals were euthanized after 3 months of suppression; the other 6 animals were euthanized after stopping ART (post 3 months suppression) when rebound plasma SIV RNA reached set-point levels. SIV DNA and RNA were measured in brain and spinal cord by qPCR. Spinal cord microglia were cultured from the ART release group to evaluate production of SIV by qRTPCR. Results: In animals euthanized after 3 months of suppressive ART, SIV DNA levels were significantly higher in lumbar spinal cord than basal ganglia (31.2 versus 0.46 median SIV copies/10x5 cells; p = 0.029, Mann-Whitney). After stopping ART and tracking rebound SIV RNA in paired plasma and CSF samples, time to initial detection of SIV RNA in plasma after stopping ART was 4 days (group median) while CSF time to first rebound was 12 days. Animals reached plasma viral load set-point (10x5-10x6 SIV copies/mL) at an average of 20 days after ART withdrawal. CSF viral loads were lower at this time-point (10x4 SIV copies/mL). To establish the source of CSF SIV RNA, qRTPCR was performed on basal ganglia and spinal cord. Whereas SIV RNA was present in spinal cord of 5 of the 6 animals (median = 1,211 SIV copy eq/ug of tissue RNA), low level SIV RNA was only detected in the brain of one animal (10 copy eq/ug tissue RNA) To identify the cellular source of SIV RNA, spinal cord microglia were cultured; culture supernatants from all 6 animals were positive for SIV RNA by qRTPCR. Conclusion: This study shows the spinal cord serves as a substantial SIV reservoir in the setting of ART. Our findings of higher levels of SIV DNA and RNA in spinal cord than brain suggest rebound SIV RNA in CSF may arise predominantly from SIV-infected spinal cord microglia rather than brain. The spinal cord merits consideration as a HIV reservoir that could challenge HIV cure efforts.

123 IMPACT OF ART REGIMENS ON CSF VIRAL ESCAPE IN HIV-1 INFECTED ADULTS Shibani S. Mukerji 1 , Vikas Misra 1 , David Lorenz 1 , Hajime Uno 1 , Susan Morgello 2 , Donald Franklin 3 , Ronald J. Ellis 3 , Scott L. Letendre 3 , Dana H. Gabuzda 1 1 Dana–Farber Cancer Institute, Boston, MA, USA, 2 Icahn School of Medicine at Mt Sinai, New York, NY, USA, 3 University of California San Diego, La Jolla, CA, USA Background: 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. Methods: 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). Results: 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

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CROI 2018