CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

682 Mx1 and OAS1-2 SNPs Are RelatedWith Severity of Liver Disease in HIV/HCV Coinfection Mónica García-Álvarez 1 ; Juan Berenguer 2 ; Daniel Pineda-Tenor 1 ; Maria Ángeles Jiménez-Sousa 1 ; María Guzmán-Fulgencio 1 ; Ana Carrero 2 ;Teresa Aldamiz-Echevarria 2 ; FranciscoTejerina 2 ; Cristina Diez 2 ; Salvador Resino 1 1 Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain; 2 Hospital General Universitario Gregorio Marañón, Madrid, Spain Background: The innate immune response against viruses induces production of interferon (IFN) type I (alpha, beta) and type III (gamma), which in turn induces the expression of genes encoding various proteins with antiviral activity, including the myxovirus resistance protein (Mx) and the family of 2’-5’-oligoadenylate synthetase (OAS) enzymes. These proteins have been linked to the progression of chronic hepatitis C. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) at Mx1 and OAS1-2 genes with the severity of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. Methods: A cross-sectional study was carried out in 219 HIV/HCV coinfected patients who had undergone liver biopsy. Genotyping of Mx1 (rs464397, rs458582 and rs469390), OAS1 rs2285934, and OAS2 rs1293762 polymorphisms were performed by using GoldenGate® assay with VeraCode® technology. The outcome variables studied were: i) significant fibrosis (METAVIR F ≥ 2); ii) moderate necroinflammatory activity grade (METAVIR A ≥ 2). The genetic association study was carried out according to a dominant model of inheritance, which was the model that best fit to our data. Results: Regarding Mx1 , the presence of F ≥ 2 was more frequent in patients with rs469390 AG/GG genotype (p=0.048). The presence of A ≥ 2 was significantly more frequent in patients with rs469390 AG/GG (p=0.017) and rs464397 CT/CC (p=0.038) genotypes. Moreover, patients with rs469390 AG/GG and rs464397 CT/CC genotypes had higher likelihood of having A ≥ 2 in liver biopsy (adjusted odds ratio (aOR)=0.48 (p=0.026) and aOR=0.45 (p=0.038), respectively). Regarding OAS1-2 , the presence of F ≥ 2 was more frequent in patients with OAS2 rs1293762 CC genotype (p=0.034). The presence of A ≥ 2 was significantly more frequent in patients with OAS1 rs2285934 CC genotype (p=0.038) and OAS2 rs1293762 CC (p=0.008). However, we only found a significant association between OAS2 rs1293762 CC genotype and the presence of A ≥ 2 in liver biopsy (aOR=2.24, p=0.015). Conclusions: Genetic polymorphisms of Mx1 (rs464397 and rs469390), OAS1 (rs2285934) and OAS2 (rs1293762) were associated with higher severity of liver disease in HIV patients coinfected with HCV. 683 Treatment With DCV Plus ASV Reduces Immune Activation in HIV/HCV Coinfected Patients Eleanor M. Wilson 4 ; Anita Kohli 3 ; Julia B. Purdy 3 ; Louisa Howard 1 ; Sabrina Mangat 1 ; GebeyehuTeferi 2 ; John Hogan 2 ; Henry Masur 3 ; Shyam Kottilil 1 1 National Institutes of Health (NIH), Bethesda, MD, US; 2 Unity Health Care, Washington, DC, US; 3 NIH, Bethesda, MD, US; 4 Leidos Biomedical Services, Inc, Bethesda, MD, US Background: HIV/HCV co-infected subjects have higher levels of immune activation and are traditionally more difficult to treat with immune-based therapy for HCV compared to those with HCV mono-infection. Directly-acting antivirals have shown promising results in treating subjects with HCV mono-infection in the absence of interferon and ribavirin. Here we describe changes in immune activation associated with rapid decline in HCV RNA levels in HIV/HCV co-infected subjects receiving treatment for HCV with daclatasvir (DCV) and asunaprevir (ASV). Methods: CONQUER is an ongoing prospective single center, phase 2 study conducted at the NIH Clinical Center of 30 HIV/HCV co-infected subjects with genotype 1 HCV, naïve to DAAs, on antiretroviral therapy with HIV viral load (VL) <50. Ten subjects with genotype 1b received DCV and ASV for 24 weeks; the next 20 genotype 1 subjects received DCV+ASV+BMS-791325 in a fixed-dose combination (FDC) for 12 weeks. HCV VL, measured using the Abbott assay, lower limit of quantification (LLOQ) 12 IU/ml; immune parameters, including CD4 + T cell counts, HLA-DR/CD38 co-expression on CD4 + and CD8 + T cells; and liver function tests were followed prospectively. Median values and interquartile range (IQR) are reported; comparisons were made using Wilcoxon Rank tests. Results: Subjects (n=10) were predominantly female (70%) and black (100%), with average age of 52 years and advanced liver disease (HAI fibrosis score <2, 40%); 20%were treatment-experienced, with previous pegylated interferon and ribavirin. HIV disease was well controlled, with HIV VL <50 on ART in 100% and average CD4 T-cell count of 855 cells/ μ L, and mean baseline HCV VL of 6.01 Log 10 IU/mL. On therapy, HCV VL was below LLOQ in 30% by Week 2 and 89% by Week 4. After 2 weeks on therapy, CD4 remained unchanged (P>0.99), while co-expression of HLADR/CD38 declined by 14% and 28% respectively on CD4 + (P=0.007) and CD8 + T cells (P=0.017), and ALT, within the normal range at baseline, decreased by an average of 51% (P=0.004).

Poster Abstracts

Conclusions: Virologically effective therapy with DCV plus ASV in HIV/HCV co-infected subjects is associated with a substantial decline in immune activation. The impact of this decline on non-AIDS defining morbidities in HIV infected subjects will need to be assessed in larger clinical studies.

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CROI 2015