CROI 2016 Abstract eBook

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Poster Abstracts

600 Intrahepatic Immune Composition Changes Markedly With Interferon-Free HCV Treatment Cody Orr 1 ; Johannes Aartun 1 ; Henry Masur 2 ; Shyam Kottilil 3 ; Eric G. Meissner 1 1 Med Univ of South Carolina, Charleston, SC, USA; 2 NIH, Bethesda, MD, USA; 3 Univ of Maryland Med Cntr, Baltimore, MD, USA

Background: Approximately 150 million people worldwide are chronically infected with hepatitis C virus (HCV), which can progress to end-stage liver disease and hepatocellular carcinoma. All oral, interferon-free treatments composed of directly activating antiviral (DAA) agents are now available. Rates of sustained virologic response (SVR) are markedly improved with DAA-based treatment, although virologic relapse after treatment still occurs in a subset of patients. Mechanisms of treatment relapse and any role of host immunity in modulating relapse risk are unclear. Methods: To understand how host immunity is impacted by treatment, and to explore immune differences that may reflect or impact outcome, we performed immunohistochemistry (IHC) on paired pre- and post-treatment liver biopsies from subjects treated in the NIH SPARE trial with sofosbuvir and ribavirin for 24 weeks who achieved SVR (n=9) or relapsed (n=4). Single-color IHC was performed with antibodies specific for CD4, CD8, CD56, CD68, CD20, TIA-1, and alpha-smooth muscle actin (ASMA) to delineate cellular populations. Image acquisition was performed on stained liver sections, followed by manual annotation of parenchymal and portal triad regions. Quantitative image analysis was performed using Visiopharm software to enumerate total pixel and cellular counts. Changes over the course of treatment were examined, and differences based on treatment outcome were explored. Results: CD8+ cells decreased markedly after DAA therapy in both parenchymal and portal triad regions irrespective of treatment outcome, similar to total HAI inflammatory score. CD20+ signal decreased in parenchymal areas while CD4+ signal decreased in portal triads. Other markers (CD56, TIA-1, KP-1, ASMA) did not change during treatment or differ by outcome. Interestingly, we observed a trend (p=0.12) toward lower pre-treatment CD4+ signal in portal triad regions of subjects who eventually relapsed compared to subjects who achieved SVR. Further delineation of CD4+ cell subtypes (i.e. T-regs, T-helper cells, etc.) was not pursued due to restricted sample availability. Conclusions: These data indicate that DAA therapy results in decreased hepatic markers of adaptive immune cells (CD8, CD4, CD20) while markers of innate immune cells (CD68, CD56), activated stellate cells (ASMA), and apoptosis (TIA-1) did not change. We describe for the first time, the nature of regression of intrahepatic chronic inflammatory response in HCV-patients receiving DAA therapy.

601 GWAS of Relapse in HIV-1/HCV Coinfected Patients TreatedWith LDV/SOF in ION-4 Sarah E. Kleinstein 1 ; Patrick R. Shea 1 ; Luisa M. Stamm 2 ; Jenny C.Yang 2 ; Philip S. Pang 2 ; Mani Subramanian 2 ; John G. McHutchison 2 ; Mark Sulkowski 3 ; DavidV. Goldstein 1 ; Susanna Naggie 4 1 Columbia Univ, New York, NY, USA; 2 Gilead Scis, Inc, Foster City, CA, USA; 3 Johns Hopkins Univ, Baltimore, MD, USA; 4 Duke Univ Sch of Med, Durham, NC, USA Background: A fixed dose combination of ledipasvir (LDV)/sofosbuvir (SOF) for 12 weeks provided high rates of sustained virologic response (SVR) in patients co-infected with HIV-1 and HCV genotype 1 or 4. In the ION-4 trial (N=335), 10 subjects had HCV relapse. All 10 subjects were African American (AA), and the majority (80%) were on efavirenz (EFV). A genome-wide association study was conducted to identify common host genetic determinants of HCV relapse after LDV/SOF therapy in HIV/HCV individuals on antiretrovirals (ARVs). Methods: All subjects consented for genetic testing (N=275) were genotyped on the Illumina HumanCore chip (~300,000 SNPs). After data quality control, 273 samples remained (8 relapse, 265 SVR). Of these, 87 samples were from AA subjects (8 relapse, 79 SVR), and 40 AA subjects were on EFV, including 6 relapse and 34 SVR. Three analyses were performed under a logistic regression model: (1) all subjects, (2) AA subjects only, and (3) AA subjects on EFV. Targeted analyses limited to drug metabolism genes were also performed. Population ancestry was corrected for by inclusion of significant ancestry principal components. The threshold for statistical significance was Bonferroni-corrected. Results: No significant genome-wide associations were observed. Although non-significant, in the AA only analysis, two SNPs were in genes of potential biological relevance to treatment failure. One SNP, rs12040970 (OR=10.97, p=6.28e-4), is intergenic, ~5kb upstream of EFNA1 , which has been linked to the GGT pathway. While rs17514846 (OR=17.74, p=0.001) is intronic in FURIN , which is induced by HCV. Both targeted analyses (see Table ) revealed the same top 3 non-coding SNPs in CYP3A4, which has been reported to interact with EFV. Further, SNPs in NR1I2 , a transcriptional regulator of CYP3A4 expression, also dominated the drug metabolism analysis. Several of these markers have plausible minor allele frequencies that are exceedingly rare in Caucasians and several fold more common among Africans. Conclusions: This study provides a comprehensive genome-wide investigation of LDV/SOF treatment relapse in HIV/HCV patients on ARVs. After accounting for multiple testing, there were no significant associations with HCV relapse. Although targeted analyses reporting on drug metabolism did show evidence of a modest association among the subset of host genes reported to interact with EFV, LDV exposure did not differ between patients who relapsed and achieved SVR.

Poster Abstracts


CROI 2016

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