CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

559 MiR-122 and -200a in Exosomes of ART+ HIV-1 Infected Individuals With Liver Disease Daniel D. Murray 1 ; Kazuo Suzuki 2 ; Matthew Law 3 ; JonelTrebicka 4 ; Jacqueline Neuhaus 5 ; DeborahWentworth 5 ; Michael J.Vjecha 6 ; Margaret Johnson 7 ; Anthony Kelleher 3 ; Sean Emery 1 ; for the INSIGHT ESPRIT and SMART Study Groups 1 Kirby Inst for Infection and Immunity in Society, Sydney, Australia; 2 Kirby Inst, Univ of New South Wales, Sydney, Australia; 3 Univ of New South Wales, Sydney, Australia; 4 Univ of Bonn, Bonn, Germany; 5 Univ of Minnesota, Minneapolis, MN, USA; 6 VA Med Cntr, Washington, DC, USA; 7 Royal Free London NHS Fndn Trust, London, UK Background: Liver disease is one of the main contributors to the increased levels of morbidity and mortality seen in the HIV-1 infected, ART-treated population. Circulating miRNAs, particularly those located inside exosomes, are seen as promising biomarkers for a number of human disease conditions including liver related diseases. Furthermore miRNAs carried in exosomes, as distinct from those bound to Argonaute proteins, are potentially functional. In a previously analysed set of 126 cases, (individuals who died whilst on therapy during the SMART and ESPRIT trials) and 247 matched controls the levels of 21 miRNAs, measured in serum, showed no associations with mortality (all-cause, cardiovascular or malignancy related). In this study we further analysed these cases and controls to determine if these miRNAs associated with liver related morbidity and mortality. Methods: Levels of the 21 circulating miRNAs were analysed, from the 373 cases and controls, to determine if there were any differences between HIV/HCV co-infected individuals (HIV/HCV) (n=82) vs HIV-mono-infected individuals (HIV-M) (n=291). Additionally levels of miRs-122, -200a and let-7e were analysed in the 13 cases who died from liver related diseases (Hepatitis C/Hepatitis B or non-viral liver failure) and compared to their 25 matched controls. Exosomes were then purified and quantified (using nanoparticle tracking analysis) from the serum of 10 of the 13 liver related cases and their 19 matched controls. MiRs-122, -200a, let-7e and cel-miR-39 were then quantified, by RTqPCR, in these samples. Results: In the SMART and ESPRIT samples there was a clear increase in serum levels of miR-122 (p<0.001) and miR-200a (p<0.001) in the HIV/HCV group compared to the HIV-M group. These same two miRNAs were also significantly elevated in the cases that died from liver related mortality compared to their matched controls (p<0.001 and p<0.01). MiR-122 was also significantly increased in the purified exosomes of the cases compared to their matched controls (p<0.01). Exosome levels of miR-200a, while not statistically significant (p=0.17), showed a six-fold increase in the median of cases compared to controls. Conclusions: These data indicate that in ART-treated individuals circulating levels of miR-122 and miR-200a are elevated and this increase is due to an increased quantity of these miRNAs inside exosomes. These miRNAs may provide novel biomarkers for liver disease, particularly HCV associated disease, in both HIV-1 and non-HIV-1 infected populations 560 Liver Fibrosis in HIV Patients: Which Factors Play a Role? Raphael Mohr 1 ; Christoph Boesecke 1 ; Carolynne Schwarze-Zander 1 ; Jan-ChristianWasmuth 1 ; Jürgen K. Rockstroh 2 1 Univ Hosp Bonn, Bonn, Germany; 2 Medizinische Univsklinik, Bonn, Germany Background: Liver-related death in HIV-infected individuals is about ten times higher compared to the general population, while the prevalence of significant liver fibrosis in HIV mono-infected patients amounts up to 15%. A better understanding of liver disease beyond the classic risk factors is needed, particularly in light of normal life expectancy under modern cART. The present study aimed to assess risk factors for development of hepatic fibrosis in HIV-patients. Methods: Health trajectory, including clinical characteristics and liver fibrosis stage assessed by transient elastography were collected at inclusion and after one year follow-up. Liver stiffness values greater than 7.1kPa were considered as significant fibrosis, while values greater than 12.5kPa were defined as severe fibrosis. Logistic regression and cox- regression uni- and multivariate analyses were performed to identify independent factors associated with liver fibrosis. Results: 432 HIV-patients were included, of which 80%were HIV mono-infected, 16%were anti-HCV-positive (54% SVR and 46% HCV-RNA positive), and 5%were HBsAg- positive. Significant liver fibrosis was detected in 10% of HIV mono-infected, in 37% of HCV and 18% of HBV co-infected patients. Patients with history of SVR after successful HCV therapy did not show a significantly higher rate of abnormal liver stiffness. The presence of diabetes mellitus (OR=5.4), adiposity (OR=4.6) and the FIB4-score (OR=3.3) were independently associated with significant fibrosis in HIV mono-infected patients. Importantly, cumulative cART duration protected, whereas persistent HIV viral replication promoted the development of significant liver fibrosis along the duration of HIV infection. After one year follow up 13% of HIV mono-infected patients presented abnormal liver stiffness values. Per treatment naive year the risk of developing significant fibrosis rose by 12%. Conclusions: Our findings strongly indicate that besides known risk factors like metabolic disorders, HIV may also have a direct effect on fibrogenesis. Successful cART leading to complete suppression of HIV replication might protect from development of liver fibrosis. 561 NASH Is AssociatedWith a Unique Biomarker Signature in HIV-Infected Adults Rebecca Krakora 1 ; Mary McLaughlin 2 ; Adam Rupert 3 ; Michael Proschan 4 ; Colleen Hadigan 2 ; David E. Kleiner 5 ;Theo Heller 6 ; Joseph A. Kovacs 1 ; Caryn G. Morse 1 1 NIH Clinical Cntr, Bethesda, MD, USA; 2 NIAID, NIH, Bethesda, MD, USA; 3 NIAID, NIH, Frederick, MD, USA; 4 NIAID, NIH, Rockville, MD, USA; 5 NCI, Bethesda, MD, USA; 6 NIDDK, Bethesda, MD, USA Background: Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are seen at high rates in HIV-infected patients. In HIV- negative populations, NAFLD is associated with visceral adiposity, increased plasma inflammatory biomarkers, and elevated risk of cardiovascular disease. This study assessed the association of NASH with plasma inflammatory biomarker levels in HIV-infected adults with NASH. Methods: Plasma levels of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6, CXCL10 (IP-10), CCL2 (MCP1), IL-8, soluble CD14 (sCD14), and soluble CD163 (sCD163), were measured in cryopreserved samples from HIV-infected adults with suppressed HIV viremia on antiretroviral therapy (ART) and liver biopsy-proven NASH (n=38), HIV-infected adults with ≥2 years of normal aminotransferases and suppressed HIV viremia on ART and no known liver disease (n=40), and HIV-negative healthy controls (n=39). Participants with current or prior diagnosis of chronic viral hepatitis were excluded. Non-parametric methods were used to compare the groups and for pairwise comparisons. Results: HIV-infected adults with NASH had elevated levels of sCD163, TNFα, CXCL10 and IL-8 compared to HIV-positive and HIV-negative control groups (p<0.001 for all comparisons). IL-6, CCL2 and sCD14 levels were elevated in HIV-infected patients (n=78) compared to HIV-negative controls but were not significantly different in HIV- infected patients with and without NASH. CRP levels did not differ between groups. Findings remained significant after adjustment for body mass index. Conclusions: In HIV-infected patients, NASH is associated with increased levels of inflammation. In other HIV-infected cohorts, elevations in these biomarkers predict non-AIDS related morbidity and mortality. The contribution of NASH to HIV-related inflammation and associated comorbidities warrants further investigation. 562 Early Mortality Risk of HIV/Hepatitis B Virus Coinfected Patients Initiating ART Mbae M. Japhet 1 ; Amos Ndhere 2 ; Stanley Ndwiga 3 ; Elisha Kirwa 4 ; RamYogev 5 ; Robert Murphy 6 ; Joseph N. Jarvis 7 1 Consolata Hosp Mathari, Nyeri, Kenya; 2 Africa Clinical Rsr Mgmt, LLC, Kisumu, Kenya; 3 Gertrude’s Children’s Hosp, Nairobi, Kenya; 4 Kenyatta Natl Hosp, Nairobi, Kenya; 5 Ann and Robert H. Lurie Children’s Hosp of Chicago, Chicago, IL, USA; 6 Northwestern Univ, Feinberg Sch of Med, Chicago, IL, USA; 7 Botswana Univ of Pennsylvania Partnership, Gaborone, Botswana Background: Hepatitis B virus (HBV) co-infection, common in HIV-infected patients in sub-Saharan Africa, is associated with impaired immunological recovery while on antiretroviral treatment (ART), and worse clinical outcomes, even in the context of effective ART. A clear association between HBV co-infection and early mortality has not been shown in African settings and the impact of tenofovir-containing ART on outcomes is unknown. Methods: The prevalence of hepatitis B surface antigen (HBsAg) was determined in a cohort of patients enrolling in an ART programme in Kenya between 2003 and 2012. Clinical outcomes, immunological and virological responses to ART were compared between HIV mono-infected and HIV/HBV co-infected patients using Cox regression. The impact of tenofovir-containing ART,phased in over the observation period, on outcomes was determined in an analysis adjusting for confounders relating to time and indication. Results: 7,155 patients were enrolled in the cohort and followed for 12,408 person years. HBsAg was detected in 451/7155 (6.3%, 95%CI 5.8-6.9%) of patients. HBsAg prevalence was higher in men than women (9.2% versus 5.0%, p<0.001) and increased with age.HBsAg positivity was associated with increased risk of death in crude analysis (HR 1.84, 95%CI 1.4-2.5, p<0.001). Among those initiating ART ( n =6,214), HBsAg positive patients ( n =419) had significantly impaired immunological recovery within the first year of ART

Poster Abstracts

221

CROI 2016