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The Liver Meeting
Washington DC
October 2017
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Survival Benefit of Direct-Acting Antiviral Therapy in Patients with Decompensated Cirrhosis
  Reported by Jules Levin
AASLD Annual Meeting 2017, Washington, DC, USA, October 20-24
W. Ray Kim1, Ajitha Mannalithara1, Haewon Lee1, Anu O. Osinusi2, Raul E. Aguilar Schall2, Diana M. Brainard2
1Division of Gastroenterology and Hepatology , Stanford University, Stanford, CA; 2Gilead Sciences, Inc., Foster City, CA


Program Abstract
Modern direct-acting antiviral (DAA) therapy in patients with decompensated HCV cirrhosis leads in the vast majority to sustained virological response, which has been associated with improvement in liver function, as measured by Child Pugh and MELD scores. However, to date, there is no evidence of improved survival. We compare the observed incidence of deaths in patients with hepatic decompensation in the SOLAR studies, phase 2 trials of sofosbuvir/ledipasvir combination, with mortality predicted by survival models derived from HCV patients with hepatic decompensation in the pre-DAA era.
Methods: Observed incidence of death was obtained from the pre-transplant cohorts of the SOLAR studies (n=212). Survival models to predict mortality without DAA therapy for 90 days and for one year were derived from liver transplant candidates with hepatic decompensation who met the SOLAR study eligibility criteria in the Organ Procurement and Transplantation Network (OPTN) data. In depicting the natural history of decompensated HCV cirrhosisin, HCV patients on the waiting list as of Jan 1, 2007 were selected to create the models and those on Jan 1, 2008 to validate them. The observed number of deaths from the start of DAA therapy was compared to the expected for 90 days and for one year by calculating the standardized mortality ratio (SMR).
Results: In the OPTN data, there were 2,071 and 899 patients for model creation and validation, respectively. The median age was 53.5 years, MELD 13, sodium 138 mEq/L and albumin 3.1 g/dL. Ascites and hepatic encephalopathy (HE) were common (78% and 65%, respectively). The optimized 90-day mortality model consisted of MELD, sodium, albumin and HE grade 3-4. The 1-year model included age, MELD, sodium, albumin, and HE grades 1-2 and 3-4. In the 2008 validation data set, the observed and predicted survival matched closely. In the SOLAR data, there were seven deaths in the first 90 days of therapy. When the 90-day survival model was applied, there was no statistically significant difference between the observed and expected (SMR=0.84, 95% confidence interval (CI): 0.40-1.77). In the Figure, there were a total of 15 deaths over one year. When compared to the predicted, the observed number of deaths was significantly lower by the 9th death (SMR=0.50, 95% CI: 0.26-0.97). By day 365, the SMR decreased further to 0.39 (95% CI: 0.24-0.65).
Conclusion: Survival of HCV patients with hepatic decompensation may be predicted accurately using the short (90 days) and longer (one year) term models. In the first 90 days of DAA therapy, there was no evidence of reduced mortality. However, beginning at approximately 4 months after therapy, the risk of death in decompensated patients receiving DAA became statistically significantly lower - as much as 61% by the end of the first year.