CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

Results: A man with HIV/AIDS [CD4: 6 cells/μL, HIV plasma viral load (VL): 716531 c/mL, CSF VL: 1200 c/mL, no DRMs] presenting with PCP, achieved prompt clinical improvement after TMP-SMX, Prednisone and cEVG/TAF/FTC initiation. 12 weeks after starting ARV, with suppressed HIV VL <40c/mL (bLOD) in plasma and CSF, he developed new ataxia and dysmetria with multiple parenchymal enhancing lesions on MRI. JCV DNA was detectable in CSF, HIV VL remained bLOD and unmasking PML-IRIS was diagnosed, which resolved with addition of Prednisone, Maraviroc and Mirtazapine. After Prednisone was tapered, PML-IRIS flared with new hand tremor: CSF analysis revealed pleocytosis with CSF HIV VL of 15441 c/mL and plasma VL to 185 c/mL. HIV genotype in CSF revealed a new E92Q DRM in Integrase (INT) and M184V/I in RT. Prednisone was restarted with clinical improvement and suppression of both plasma and CSF HIV VL bLOD. Follow-up monitoring of plasma VL showed a progressive increase up to 509 c/mL with the new appearance of E92Q INT and M184I/V RT in plasma. Retrospective drug level analysis documented subtherapeutic EVG concentration in CSF (5.5 ng/ml), which was >300 fold lower than concurrent plasma EVG (1730 ng/mL). Robust specific CD4 T cells responses to JCV, but not to BKV or CMV were documented in CNS and peripheral blood at the time of PML-IRIS flare Conclusion: Rebound viremia with DRMs emerged in the setting of CNS immune activation from PML-IRIS and suboptimal CSF EVG levels. HIV-1 RNA was >100 fold higher in CSF than plasma, suggesting selection of resistant variants in CNS and consequent dissemination to peripheral blood and lymphnode. The case highlights the role of localized inflammatory processes and trafficking of immune cells in shaping HIV populations in CNS, plasma and lymphoid tissue

neurological symptoms and magnetic resonance imaging (MRI) white matter changes, and it is usually reverted upon cART optimization. Our aimwas to identify and characterize possible cases of relapse in the long-term follow-up. Methods: A cohort of 21 cases of symptomatic CSF escape was followed between 2003 and 2017. Cases were defined as onset of new neurological symptoms and/or signs in cART-treated patients with HIV-RNA detectable in CSF, but not in plasma, or CSF HIV-RNA higher than plasma level. Relapse was defined as the re-occurrence of symptomatic CSF escape following clinical and, when follow-up CSF sample of first episode was available, virological regression of first episode. Results: In the 21 CSF escape cases, median CSF HIV-RNA was 1056 c/mL (IQR 63-75,000); plasma HIV-RNA was detectable in 10 of 21 patients, median 1055 c/mL (IQR 92-8194); cognitive impairment was observed in 12 patients and cerebellar symptoms in 11. MRI demonstrated diffuse bilateral white matter hyperintensities on T2-weighted sequences in 15 of 20 patients. During a median follow-up of 66 months (range 12-121) after cART optimization, CSF escape relapsed in 5 of 21 cases (24%) as a consequence of cART simplification, which included zidovudine (AZT) withdrawal, in 3, or poor adherence in 2 (Table). CSF resistance mutations were identified in 2 cases. There were no significant differences between first escape and relapse as for current CD4+ cells (median 300 vs. 722/µL), CSF HIV-RNA (median 1000 vs. 853 c/mL), HIV-RNA detectability in plasma (40% vs. 60%), clinical and MRI findings. cART re-optimization according to resistance profile and/or predicted neuropenetration, including AZT in 3 patients, lead to clinical resolution in all patients and HIV-RNA clearance in all of the tested cases. At last follow-up, 3 patients had underwent cART simplification, either maintaining AZT (n=1), or switching to a new dolutegravir-containing regimen without AZT (n=2), with no new escape episodes. Conclusion: CSF escape may relapse months to years after recovery, if cART efficacy in the CNS is weakened by simplification or loss of adherence. These observations also support, at least in some patients, the presence of a viral reservoir within the CNS.

Poster Abstracts

449 DEEP SEQUENCING REVEALS EXTENSIVE CSF COMPARTMENTALIZATION IN HIV+ PEOPLE IN UGANDA Sarah B. Joseph 1 , Deanna Saylor 2 , Gertrude Nakigozi 3 , Noeline Nakasujja 4 , Kevin Robertson 1 , Ronald H. Gray 2 , Maria Wawer 2 , Ronald Swanstrom 1 , Ned Sacktor 2 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 Johns Hopkins University, Baltimore, MD, USA, 3 Rakai Health Sciences Program, Kalisizo, Uganda, 4 Makerere University, Kampala, Uganda Background: Sustained viral replication and evolution in a tissue can produce compartmentalized viral lineages that are genetically distinct from populations in the blood. Compartmentalized viral populations have previously been observed in the cerebrospinal fluid (CSF) of individuals infected with subtype B HIV-1, particularly those with HIV-associated dementia (HAD). Less is known about rates of CSF compartmentalization in individuals infected with other viral subtypes and/or lacking severe neurocognitive disorders. HIV-1 replication in the CNS is thought to contribute to neurocognitive impairment in HIV-infected people, but this hypothesis has not been previously examined. Methods: 50 antiretroviral-naïve HIV+ individuals were enrolled in Rakai, Uganda and assessed with a neuromedical examination, neuropsychological test battery, and functional status assessments to define HAND staging based on Frascati criteria. Viral RNA was isolated from plasma and CSF samples, and Illumina MiSeq deep sequencing with Primer ID was used to sequence env V1-V3. A neighbor joining phylogenetic tree was constructed for each person to compare HIV-1 populations in the CSF and blood. Phylogenetic trees were visually examined and CSF compartmentalization identified when approximately half or more of the CSF sequences formed lineages that were genetically distinct from blood sequences.

448 CNS ESCAPE OF DRUG-RESISTANT HIV IN PML-IRIS AND CONSEQUENT PERIPHERAL DISSEMINATION Andrea Lisco 1 , Camille Lange 2 , Bryan Smith 3 , Maura Manion 1 , Natalie Lindo 2 , Dima A. Hammoud 1 , Catherine A. Rehm 1 , Alice K. Pau 1 , Safia S. Kuriakose 4 , Megan Anderson 1 , Pawel Muransky 5 , Craig Sykes 6 , Frank Maldarelli 2 , Irini Sereti 7 1 NIAID, Bethesda, MD, USA, 2 National Cancer Institute, Frederick, MD, USA, 3 National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA, 4 Leidos Biomedical Research, Inc, Frederick, MD, USA, 5 Columbia University Medical Center, New York, NY, USA, 6 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 7 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA Background: Inflammation and tissue influx of activated T cells affects the compartmentalization and dynamics of HIV viral replication, but the role of compartmentalized virus populations in the emergence of drug resistant mutations (DRMs) and virological failure is uncertain. Herein, we describe viral escape with high viral RNA levels and DRMs in CSF during an episode of unmasking PML-IRIS Methods: PBMCs and CSF mononuclear cells were used for immunophenotyping along with a flow cytometric T cells responses assay to JC virus (JCV), BKV and CMV. Plasma and CSF ARV concentrations were measured by tandemmass spectrometry. Phylogenetic analysis of CSF, plasma, rectal mucosa and cervical lymph node HIV variants was performed

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