ALBERT

Description: Background: Complications from chronic hepatitis C virus (HCV) infection are a major cause of morbidity and mortality among individuals with inherited blood disorders (IBLD). Inability to tolerate ribavirin and frequent comorbidities have limited HCV treatment options in these patients. The aim of the C-EDGE IBLD study was to evaluate the efficacy and safety of a once-daily, fixed-dose combination of elbasvir 50 mg (EBR, an NS5A inhibitor) and grazoprevir 100 mg (GZR, an NS3/4A protease inhibitor) in patients with HCV infection and IBLD, including those with hemoglobinopathies. Methods: C-EDGE-IBLD was a randomized, double-blind, placebo-controlled study of treatment-naïve and treatment-experienced patients with HCV genotype (GT)1, 4, or 6 infection and IBLD (hemophilia A/B, von Willebrand disease, β-thalassemia, or sickle cell anemia). Patients were randomized in a 2:1 ratio to an immediate-treatment group (ITG; 12 weeks of EBR/GZR) or deferred-treatment group (DTG; 12 weeks of placebo, followed by EBR/GZR for 12 weeks). Randomization was stratified according to the presence of cirrhosis and IBLD diagnosis. The primary endpoints were the proportion of patients in the ITG who achieved sustained virologic response (SVR12, HCV RNA 3× baseline and 〉100 U/L). In the EBR/GZR treatment phase of the DTG (n = 49), 3 patients reported serious adverse events; none were drug-related and 2 were related to IBLD. Conclusions: Final data from the C-EDGE IBLD study indicate that EBR/GZR is well tolerated and effective in patients with HCV GT1 or 4 infection with IBLD. Disclosures Hézode: BMS: Consultancy; Janssen: Consultancy; MSD: Consultancy; AbbVie: Consultancy; Gilead: Consultancy. Fried:NIH: Research Funding; Gilead: Consultancy, Research Funding; TARGET PharmaSolutions: Equity Ownership; Merck: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Colombo:Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tibotec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Vertex: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GenSpera: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AlfaWasserman: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jennerex: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intercept: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bourlière:MSD: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Janssen: Consultancy; GSK: Consultancy; BMS: Consultancy. Ben-Ari:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Strasser:MSD/Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Norgine: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria. Perumalswami:Merck: Research Funding; Gilead: Research Funding. Zamor:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Eli Lilly: Consultancy; BMS: Research Funding; Gilead: Research Funding; Sanofi: Consultancy; Merck: Research Funding; Novartis: Consultancy. Satoskar:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Research Funding. Sherman:AbbVie: Research Funding; Gilead: Research Funding; BMS: Research Funding; Merck: Consultancy, Research Funding. Morgan:Merck & Co., Inc.: Employment, Equity Ownership. Qiu:Merck: Employment. Hwang:Merck: Employment, Equity Ownership. Robertson:Merck: Employment, Equity Ownership. Nguyen:Merck: Employment. Barr:Merck: Employment, Equity Ownership. Wahl:Merck: Employment. Haber:Merck: Employment. Chase:Merck: Employment. Talwani:Merck & Co., Inc: Employment. Di Marco:Gilead: Research Funding.

Description: Patients with inherited bleeding disorders who received clotting factor concentrates before 1987 have high rates of hepatitis C virus (HCV) or HCV/HIV infection. We evaluated HCV quasispecies evolution in longitudinally collected specimens comparing those from patients with progression to end-stage liver disease (ESLD; cases) to those with compensated chronic hepatitis (controls). Plasma samples were obtained from the National Cancer Institute Multicenter Hemophilia Cohort Study. Controls were matched for age, sex, infection duration, and presence/absence of HIV. Samples from early infection were compared to those obtained after onset of ESLD in the cases. The first hypervariable (HVR1) and core proteincoding regions were amplified, subcloned, and sequenced. Complexity and diversity were determined. More than 700 sub-clones from 10 pairs of patients (8 with HIV) followed over approximately 9.3 years were evaluated. HVR1 complexity narrowed over time in the cases, whereas it increased in controls (P = .01). Similar trends were observed for diversity within HVR1 and the core region (P = .04). HCV-infected patients with inherited bleeding disorders undergo quasispecies evolution over time. Evolution patterns differ for progressors and nonprogressors. Further understanding of these mechanisms may help identify factors related to progression rate and treatment response.

Description: Introduction: Hepatitis C is the leading cause of liver disease in individuals with hemophilia (H). HIV co-infection in 80% accelerates HCV disease progression. Although antiretroviral therapy improves HIV survival and slows HCV progression, some ultimately require transplantation. In contrast to non-hemophilic (NH) risk groups, H have 1) longer duration HCV infection with HCV acquisition via clotting factor in the first year of life; and 2) greater bleeding risk due to factor VIII (IX) deficiency in the setting of thrombocytopenia in end-stage liver disease. These risks are important as 1) duration of HCV infection is a significant predictor of liver disease progression; and 2) increased bleeding risk, including gastrointestinal bleeding, increases post-transplant mortality. Several studies have shown that, while post-transplant survival is similar, pre-transplant survival is shorter in HIV/HCV+ H than NH candidates. These studies were small, limiting analysis for predictors of pre-transplant survival. Methods: We conducted a retrospective observational study utilizing United Network for Organ Sharing (UNOS) national transplant registry data, comparing HCV+ H and HCV+ NH candidates. A 7-item case report form was completed on each subject by eight respective transplant centers including 1) hemophilia status (hemophilia A, ICD 286.0; hemophilia B, ICD 286.1); 2) hepatocellular carcinoma status; 3) HIV status; 4) CD4+ count; 5) HIV RNA PCR; 6) HCV RNA PCR; and 7) platelet count, the latter four variables at listing and at transplantation. We performed univariate proportional hazards models for pre-transplant mortality within 90 days of listing, including group and baseline factors. Variables with p