AIM: To determine risk factors associated with hepatitis C virus(HCV) treatment failure after direct acting antivirals in patients with complex treatment histories.METHODS: All HCV mono-infected patients who received treatment at our institution were queried.Analysis was restricted to patients who previously failed treatment with boceprevir(BOC) or telaprevir(TVR) and started simeprevir(SMV) and sofosbuvir(SOF) ± ribavirin(RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus(HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December,31 st 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics,HCV infection,and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF.RESULTS: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon(PEG) and RBV who failed this triple therapy were subsequently retreated with an off-label all-oral regimen of SMV and SOF for 12 wk,with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response,but later relapsed. Eight(100%) patients were male. Mean age was 56(range,49-64). Eight(100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6(mean 3.8). Eight(100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven(87.5%) patients had genotype 1a HCV. Seven(87.5%) patients had over 1 million IU/m L HCV RNA at the time of re-treatment.CONCLUSION: This study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high-titer genotype 1a HCV. AIM: To determine risk factors associated with hepatitis C virus (HCV) treatment failure after direct acting antivirals in patients with complex treatment histories. METHHODS: All HCV mono-infected patients who received treatment at our institution were queried. Analysis was restricted to patients who previously failed treatment with boceprevir (BOC) or telaprevir (TVR) and started simeprevir (SMV) and sofosbuvir (SOF) ± ribavirin (RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus (HIV) / HCV co-infection or patients who received a liver transplant in the past were excluded. Data collection continued until December, 31 st 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF / SOF but late r relapsed. Data related to patient demographics, HCV infection, and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF / SOF.RESULTS: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon (PEG) and RBV who failed retreated with an off-label all-oral regimen of SMV and SOF for 12 wk, with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV / SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response, but later relapsed. Eight (100%) patients were male. Mean age was 56 (range, 49-64 ) Eight (100%) patients had previously failed PEG / RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6 (mean 3.8). Eight male had liver cirrhosis as determ iSeven (87.5%) patients had over 1 million IU / m L HCV RNA at the time of re-treatment. CONCLUSION: This study identifies factors associated with SMV / SOF treatment failure and can evidence the twleve weeks of SMV / SOF / RBV is insufficient in cirrhotics with high-titer genotype 1a HCV.