CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

74 GENETIC VARIATION IN EIF2AK3 IS ASSOCIATED WITH NEUROCOGNITIVE IMPAIRMENT IN HIV Scott Letendre 1 , Cagla Akay-Espinoza 2 , Ajay Bharti 1 , Peilin Jia 3 , Asha R. Kallianpur 4 , Donald Franklin 1 , Gerard D. Schellenberg 2 , Robert K. Heaton 5 , Igor Grant 5 , Kelly L. Jordan-Sciutto 2 1 Univ of California San Diego, San Diego, CA, USA, 2 Univ of Pennsylvania, Philadelphia, PA, USA, 3 Univ of Texas Houston, Houston, TX, USA, 4 Cleveland Clinic Lerner Coll of Med, Cleveland, OH, USA, 5 Univ of California San Diego, La Jolla, CA, USA Background: Despite its continued high prevalence, genetic vulnerability to HIV-associated neurocognitive impairment (NCI) remains less well understood than in the general population. Risk factors for NCI (e.g., HIV replication, persistent inflammation) can induce the ubiquitous unfolded protein response (UPR), which activates initiator proteins that can phosphorylate eukaryotic translation initiation factor 2α (eIF2α) and subsequently, slow global translation initiation while selectively increasing translation of transcripts such as β-site amyloid precursor protein cleaving enzyme-1. Chronic UPR activation has been implicated in Alzheimer’s and Parkinson’s diseases. We evaluated associations of single nucleotide polymorphisms (SNPs) in the EIF2AK3 gene with neurocognitive (NC) performance of HIV+ adults. Methods: 1,047 participants from CHARTER’s Genome-Wide Association Study (GWAS) were randomly assigned 1:1 to either a Test set or a Validation set. Using a candidate gene approach, 3 SNPs in the EIF2AK3 gene (rs6739095, rs1913671, rs11684404) were compared to the Global Deficit Score (GDS) and Global NCI using routine univariate and multivariable methods to adjust for confounding conditions. Results: Median age was 43; 23%were women; 34% had European ancestry and 42% had African ancestry; 61% had AIDS; median CD4+ counts were 175 (nadir) and 428 (current); and 71% used antiretroviral therapy (ART) with 58% having plasma HIV RNA ≤ 50 c/mL. For rs6739095, 42% had ≥1 T allele; for rs1913671, 41% had ≥1 C allele; and for rs11684404, 39% had ≥1 C allele. Findings were similar in the Test and the Validation sets, e.g., rs11684404 was associated with GDS in a allelic dose manner (genotype- median GDS): CC-0.32, CT-0.37, TT-0.42 (p=0.032 (Test), 0.035 (Validation)). In the combined group, TT homozygotes had 46% higher risk of NCI than CC homozygotes (p=0.01). Associations of rs11684404 with either GDS or NCI persisted after multivariable adjustment (model p<0.0001). Those with non-European ancestry had stronger associations between these SNPs and GDS or NCI [e.g., 61% higher risk for rs11684404 TT than CC homozygotes (p=0.02)]. Conclusion: Variation in EIF2AK3 was associated with NC performance, with consistent effects in both test-validation and multivariable analyses, supporting the importance of UPR in HIV neuropathogenesis. EIF2AK3, and perhaps other UPR-related genes, may contribute to NCI risk in HIV+ adults. 75 CEREBRAL SMALL-VESSEL DISEASE IN HIV-INFECTED PATIENTS WELL CONTROLLED ON CART Antoine Moulignier 1 , Julien Savatovsky 1 , Ophélia Godin 2 , Nadia Valin 3 , François-Xavier Lescure 4 , Roland Tubiana 5 , Ana Canestri 6 , Cédric Lamirel 1 , Dominique Costagliola 2 , for the MICROBREAK ANRS Study Group 1 Fndn Ophtalmologique Adolphe de Rothschild, Paris, France, 2 Univ Paris 06, Paris, France, 3 Saint Antoine Hosp, Paris, France, 4 Bichat Hosp, Paris, France, 5 Pitié-Salpétrière Hosp, Paris, France, 6 Tenon Hosp, Paris, France Background: Cerebral small vessel disease (CSVD), defined by white matter hyperintensities (WMHs), silent brain infarction (SBI) or microbleeds (MBs), is a major cause of future vascular events, cognitive impairment, frailty, and poor survival. CSVD is correlated with age and cardiovascular risk factors (CVRF). Little is known on the prevalence of CSVD in persons living with HIV (PLWHIV) with controlled viral load (VL) under cART, who often present conventional and non-conventional CVRFs. Methods: The ANRS EP51 MICROBREAK (NCT02082574) cross-sectional study, conducted in 4 Paris hospitals in France, aimed to assess the prevalence of CSVD detected by MRI in treated PLWHIV, 50 years of age or older, not HCV infected and with controlled VL for at least 12 months, in comparison with HIV negative controls (HNC), with frequency matching on age and sex. Brain 3T MRI included 3D FLAIR, DWI and T2*. All MRI were reviewed by 2 experienced neuroradiologists, blinded to HIV status, using the Fazekas scale for WMHS and Wardlaw’s research criteria for SBI and MBs, with a third reader in case of discordance. We also assessed the impact of HIV on the severity of CSVD defined as WMHs Fazekas 2-3 or SBI or MBs. A logistic regression model was used to assess the impact of HIV on CSVD adjusted on traditional risk factors. Results: Between June 2013 and May 2016, 456 PLWHIV and 154 HNC were recruited; median age was 56 and 58 years (p=0.001), 84% and 77% (p=0.030) were men, respectively. All CVRF were more frequent in PLWHIV than in HNC (hypertension 33% vs 21%, hypercholesterolemia 41% vs 19% and hypertriglyceridemia 22% vs 6%, respectively), except diabetes (8% vs 5%) and smoking (46% vs 42%). The median CD4 count in PLWHIV was 655/mm3 [IQR: 510 - 845] and 62% had been diagnosed before 1996. CSVD was detected in 51.5% of PLWHIV and 36.4% of HNC, with an adjusted odds ratio (ORa) of 2.3 (95% confidence interval: 1.5–3.6). Severe CSVD was observed in 19% of PLWHIV and 14% of HNC, with an ORa of 1.6 (0.9–2.7). As expected, older age and hypertension were also associated with the risk of CSVD. The impact of HIV was different according to age, with ORa of 5.3 (1.7–16.3), 3.7 (1.7–8.0) and 1.0 (0.5–2.2) for age of <54, 54-60 and >60 years, respectively (p=0.022). Conclusion: Despite cART-sustained immunovirologic control, the prevalence of CSVD is twice higher in middle-aged PLWHIV. Besides age and hypertension, HIV is an independent risk factor of CSVD. 76LB A MULTICENTER DIAGNOSTIC ACCURACY STUDY OF THE XPERT ULTRA FOR TUBERCULOSIS DIAGNOSIS Samuel G. Schumacher 1 , Pamela Nabeta 1 , Catharina C. Boehme 1 , Jerrold Ellner 2 , David Alland 3 , Susan E. Dorman 4 , Claudia M. Denkinger 1 , for the TB Clinical Diagnostics Research Consortium and FIND Trial Consortium 1 FIND, Geneva, Switzerland, 2 Boston Med Cntr, Boston, MA, USA, 3 Univ of Med and Dentistry of New Jersey, Newark, NJ, USA, 4 Johns Hopkins Univ, Baltimore, MD, USA Background: The development of the Xpert MTB/RIF (Xpert) was a major step forward for improving tuberculosis (TB) and rifampin (RIF) diagnosis globally. However, Xpert sensitivity is imperfect in smear-negative and HIV-associated TB and some limitations also remain in the determination of RIF-resistance status. The Xpert Ultra (Ultra) has been developed as the next-generation assay to overcome these limitations. Methods: This was a prospective multicenter diagnostic accuracy study in adults with signs/symptoms of pulmonary TB. Xpert and Ultra were performed from the same specimen and accuracy determined with four cultures as the reference standard for TB detection (two MGIT tubes + two LJ slants, performed on two specimens obtained on separate days) and phenotypic drug-susceptibility testing for RIF resistance detection. Results: 1,520 patients were enrolled in 10 sites across 8 countries. Sensitivity of the Ultra was 5% higher than that of Xpert (95%CI +2.7, +7.8) but specificity was 3.2% lower (95%CI -2.1, -4.7). Sensitivity-increases were higher among smear-negative patients (+17%, 95%CI +10, +25) and among HIV-infected patients (+12%, 95%CI +4.9, +21). Specificity-decreases were higher in patients with a history of TB (-5.4%, 95%CI -9.1, -3.1) than in patients with no history of TB (-2.4%, 95%CI -4.0, -1.3). Reclassifying ‘trace calls’ (the semi-quantitative category of the Ultra assay that corresponds to the lowest bacillary burden) as ‘TB-negative’-either in all cases or in those with a history- mitigates some of the specificity losses (Specificity –1.0%/-1.9% if trace reclassified for all cases/cases with history) while maintaining some of the sensitivity gains over Xpert (Sensitivity +7.6%/+15%). Ultra classified more patients correctly as RIF-resistant (+1.1%, 95%CI -2.0, +4.6) and RIF-sensitive (+2.6%, 95%CI +0.2, +5.2) overall because the Xpert missed TB in patients with very paucibacillary disease entirely. Conclusion: Ultra has higher sensitivity than Xpert in smear-negative and HIV-infected patients and improved accuracy for RIF detection. However, as a result of the increased sensitivity, Ultra also detects TB DNA in some patients with prior TB disease, possibly due to persistence of non-viable bacilli, leading to reduced specificity. Similar results can be expected for other upcoming next-generation molecular TB assays. A discussion of resulting implementation challenges and the willingness to trade off specificity for increased sensitivity in different settings is urgently needed.

Oral Abstracts

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CROI 2017