Browsing by Author "Watt, Kymberly D."

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    Circulating Extracellular Vesicles Carrying Sphingolipid Cargo for the Diagnosis and Dynamic Risk Profiling of Alcoholic Hepatitis
    (Wolters Kluwer, 2021) Sehrawat, Tejasav S.; Arab, Juan P.; Liu, Mengfei; Amrollahi, Pouya; Wan, Meihua; Fan, Jia; Nakao, Yasuhiko; Pose, Elisa; Navarro-Corcuera, Amaia; Dasgupta, Debanjali; Liao, Chieh-Yu; He, Li; Mauer, Amy S.; Avitabile, Emma; Ventura-Cots, Meritxell; Bataller, Ramon A.; Sanyal, Arun J.; Chalasani, Naga P.; Heimbach, Julie K.; Watt, Kymberly D.; Gores, Gregory J.; Gines, Pere; Kamath, Patrick S.; Simonetto, Douglas A.; Hu, Tony Y.; Shah, Vijay H.; Malhi, Harmeet; Medicine, School of Medicine
    Background and aims: Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. Approach and results: EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end-stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol-associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 1011 /mL) compared to healthy controls (4.38 × 1010 /mL; P < 0.0001), heavy drinkers (1.28 × 1011 /mL; P < 0.0001), ESLD (5.35 × 1010 /mL; P < 0.0001), and decompensated AC (9.2 × 1010 /mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End-Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high-EV group and 90.0% in the low-EV group (log-rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. Conclusions: Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90-day survival permitting dynamic risk profiling.
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    Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease
    (Elsevier, 2015-09) Charlton, Michael; Everson, Gregory T.; Flamm, Steven L.; Kumar, Princy; Landis, Charles; Brown, Robert S., Jr.; Fried, Michael W.; Terrault, Norah A.; O'Leary, Jacqueline G.; Vargas, Hugo E.; Kuo, Alexander; Schiff, Eugene; Sulkowski, Mark S.; Gilroy, Richard; Watt, Kymberly D.; Brown, Kimberly; Kwo, Paul; Pungpapong, Surakit; Korenblat, Kevin M.; Muir, Andrew J.; Teperman, Lewis; Fontana, Robert J.; Denning, Jill; Arterburn, Sarah; Dvory-Sobol, Hadas; Brandt-Sarif, Theo; Pang, Phillip S.; McHutchison, John G.; Reddy, K. Rajender; Afdhal, Nezam; Department of Medicine, IU School of Medicine
    Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation.