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2. Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients

Author

Lawitz, Eric J, Li, Kelvin W, Nyangau, Edna, Field, Tyler John, Chuang, Jen-Chieh, Billin, Andrew, Wang, Lulu, Wang, Ya, Huss, Ryan S, Chung, Chuhan, Subramanian, G Mani, Myers, Robert P, and Hellerstein, Marc K

Subjects
Liver Disease, Biomedical Imaging, Chronic Liver Disease and Cirrhosis, Clinical Research, Hepatitis, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Acetyl-CoA Carboxylase, Biomarkers, Carbon, Deuterium Oxide, Fibrosis, Humans, Lipogenesis, Lipoproteins, VLDL, Liver, Liver Cirrhosis, Non-alcoholic Fatty Liver Disease, Palmitates, Triglycerides, Fatty acid synthesis, nonalcoholic fatty liver disease, NASH, tracer kinetics, stable isotope use in humans, triglycerides, de novo lipogenesis, mass spectrometry, acetyl-CoA carboxylase inhibition, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract

De novo lipogenesis (DNL) converts carbon substrates to lipids. Increased hepatic DNL could contribute to pathogenic liver triglyceride accumulation in nonalcoholic steatohepatitis (NASH) and therefore may be a potential target for pharmacological intervention. Here, we measured hepatic DNL using heavy water in 123 patients with NASH with fibrosis or cirrhosis, calculated the turnover of hepatic triglycerides to allow repeat labeling studies, and determined the associations of hepatic DNL with metabolic, fibrotic, and imaging markers. We found that hepatic DNL was higher in patients with fibrotic NASH [median (IQR), 40.7% contribution to palmitate (32.1, 47.5), n=103] than has been previously reported in healthy volunteers and remained elevated [median (IQR), 36.8% (31.0, 44.5), n=20] in patients with cirrhosis, despite lower liver fat content. We also showed that turnover of intrahepatic triglyceride pools was slow (t½ >10 days). Furthermore, DNL contribution was determined to be independent of liver stiffness by magnetic resonance imaging but was positively associated with the number of large very low density lipoprotein (VLDL) particles, the size of VLDL, the lipoprotein insulin resistance score, and levels of ApoB100, and trended toward negative associations with the fibrosis markers FIB-4, FibroSure, and APRI. Finally, we found treatment with the acetyl-CoA carboxylase inhibitor firsocostat reduced hepatic DNL at 4 and 12 weeks, using a correction model for residual label that accounts for hepatic triglyceride turnover. Taken together, these data support an important pathophysiological role for elevated hepatic DNL in NASH and demonstrate that response to pharmacological agents targeting DNL can be correlated with pretreatment DNL.

Published
2022

4. Methylation signatures in peripheral blood are associated with marked age acceleration and disease progression in patients with primary sclerosing cholangitis.

Author

Trauner, Michael, Gindin, Yevgeniy, Jiang, Zhaoshi, Chung, Chuhan, Subramanian, G Mani, Myers, Robert P, Gulamhusein, Aliya, Kowdley, Kris V, Levy, Cynthia, Goodman, Zachary, Manns, Michael P, Muir, Andrew J, and Bowlus, Christopher L

Subjects
ALP, alkaline phosphatase, ALT, alanine aminotransferase, Aging, BMI, body mass index, DNAm, DNA methylation, ELF, enhanced liver fibrosis, FDR, false discovery rate, GGT, gamma-glutamyltransferase, IBD, inflammatory bowel disease, IL, interleukin, LOXL2, lysyl oxidase-like-2, NASH, non-alcoholic steatohepatitis, PSC, primary sclerosing cholangitis, SMA, smooth muscle actin, UDCA, ursodeoxycholic acid, biomarker, inflammatory bowel disease, primary sclerosing cholangitis, prognosis, ursodeoxycholic acid, ALP, alkaline phosphatase, ALT, alanine aminotransferase, BMI, body mass index, DNAm, DNA methylation, ELF, enhanced liver fibrosis, FDR, false discovery rate, GGT, gamma-glutamyltransferase, IBD, IL, interleukin, LOXL2, lysyl oxidase-like-2, NASH, non-alcoholic steatohepatitis, PSC, SMA, smooth muscle actin, UDCA
Abstract

Background & Aims:A DNA methylation (DNAm) signature derived from 353 CpG sites (the Horvath clock) has been proposed as an epigenetic measure of chronological and biological age. This epigenetic signature is accelerated in diverse tissue types in various disorders, including non-alcoholic steatohepatitis, and is associated with mortality. Here, we assayed whole blood DNAm to explore age acceleration in patients with primary sclerosing cholangitis (PSC). Methods:Using the MethylationEPIC BeadChip (850K) array, DNAm signatures in whole blood were analyzed in 36 patients with PSC enrolled in a 96-week trial of simtuzumab (Ishak F0-1, n = 13; F5-6, n = 23). Age acceleration was calculated as the difference between DNAm age and chronological age. Comparisons between patients with high and low age acceleration (≥ vs. < the median) were made and Cox regression evaluated the association between age acceleration and PSC-related clinical events (e.g. decompensation, cholangitis, transplantation). Results:Age acceleration was significantly higher in patients with PSC compared to a healthy reference cohort (median, 11.1 years, p

Published
2020

5. Plasma eicosanoids as noninvasive biomarkers of liver fibrosis in patients with nonalcoholic steatohepatitis.

Author

Caussy, Cyrielle, Chuang, Jen-Chieh, Billin, Andrew, Hu, Tao, Wang, Ya, Subramanian, G Mani, Djedjos, C Stephen, Myers, Robert P, Dennis, Edward A, and Loomba, Rohit

Subjects
HETE, HETRE, NAFLD, NASH, adrenic acid, arachidonic acid, eicosanoids, fibrosis, lipidomics, liver, Clinical Research, Hepatitis, Clinical Trials and Supportive Activities, Digestive Diseases, Liver Disease, Chronic Liver Disease and Cirrhosis, Oral and gastrointestinal, Good Health and Well Being, Clinical Sciences, Pharmacology and Pharmaceutical Sciences
Abstract

BackgroundEicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepatitis (NASH). Therefore, we investigated associations between plasma eicosanoids and liver fibrosis to evaluate their utility in diagnosing and monitoring NASH-related fibrosis.MethodsOur analysis used baseline eicosanoid data from 427 patients with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), and longitudinal measurements along with liver fibrosis staging from 63 patients with NASH and stage 2/3 fibrosis followed for 24 weeks in a phase II trial.ResultsAt baseline, four eicosanoids were significantly associated with liver fibrosis stage: 11,12-DIHETE, tetranor 12-HETE, adrenic acid, and 14, 15-DIHETE. Over 24 weeks of follow up, a combination of changes in seven eicosanoids [5-HETE, 7,17-DHDPA, adrenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), 16-HDOHE, and 9-HODE) had good diagnostic accuracy for the prediction of ⩾1 stage improvement in fibrosis (AUROC: 0.74; 95% CI: 0.62-0.87), and a combination of four eicosanoids (7,17-DHDPA, 14,15-DIHETRE, 9-HOTRE, and free adrenic acid) accurately predicted improvement in hepatic collagen content (AUROC: 0.72; 95% CI: 0.50-0.77).ConclusionThis study provides preliminary evidence that plasma eicosanoids may serve as noninvasive biomarkers of liver fibrosis and may predict liver fibrosis improvement in NASH.

Published
2020

7. The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS‐9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis

Author

Trauner, Michael, Gulamhusein, Aliya, Hameed, Bilal, Caldwell, Stephen, Shiffman, Mitchell L, Landis, Charles, Eksteen, Bertus, Agarwal, Kosh, Muir, Andrew, Rushbrook, Simon, Lu, Xiaomin, Xu, Jun, Chuang, Jen‐Chieh, Billin, Andrew N, Li, Georgia, Chung, Chuhan, Subramanian, G Mani, Myers, Robert P, Bowlus, Christopher L, and Kowdley, Kris V

Subjects
Liver Disease, Chronic Liver Disease and Cirrhosis, Clinical Research, Clinical Trials and Supportive Activities, Digestive Diseases, Rare Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Oral and gastrointestinal, Administration, Oral, Adult, Alkaline Phosphatase, Analysis of Variance, Aspartate Aminotransferases, Biomarkers, Cholangitis, Sclerosing, Cholestasis, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Humans, Liver Function Tests, Logistic Models, Male, Middle Aged, Prognosis, Receptors, Cytoplasmic and Nuclear, Reference Values, Severity of Illness Index, Treatment Outcome, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology
Abstract

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double-blind, placebo-controlled study, we tested the safety and efficacy of cilofexor (formerly GS-9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large-duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α-hydroxy-4-cholesten-3-one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288-439) and 0.7 mg/dL (0.5-1.0), respectively. Dose-dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction -21%; P = 0.029 versus placebo), gamma-glutamyl transferase (-30%; P < 0.001), alanine aminotransferase (ALT) (-49%; P = 0.009), and aspartate aminotransferase (-42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid-treated and untreated patients. At week 12, cilofexor-treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, tissue inhibitor of metalloproteinase 1, C-reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo-treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12-week, randomized, placebo-controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.

Published
2019

8. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib

Author

Jayakumar, Saumya, Middleton, Michael S, Lawitz, Eric J, Mantry, Parvez S, Caldwell, Stephen H, Arnold, Hays, Diehl, Anna Mae, Ghalib, Reem, Elkhashab, Magdy, Abdelmalek, Manal F, Kowdley, Kris V, Djedjos, C Stephen, Xu, Ren, Han, Ling, Subramanian, G Mani, Myers, Robert P, Goodman, Zachary D, Afdhal, Nezam H, Charlton, Michael R, Sirlin, Claude B, and Loomba, Rohit

Subjects
Digestive Diseases, Hepatitis, Substance Misuse, Clinical Research, Chronic Liver Disease and Cirrhosis, Liver Disease, Biomedical Imaging, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Oral and gastrointestinal, Good Health and Well Being, Adolescent, Adult, Aged, Benzamides, Biopsy, Disease Progression, Dose-Response Relationship, Drug, Elasticity Imaging Techniques, Female, Humans, Imidazoles, Injections, Subcutaneous, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Pyridines, ROC Curve, Reproducibility of Results, Treatment Outcome, Young Adult, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Hepatic steatosis, Non-invasive tests, Liver biopsy, Clinical Sciences, Public Health and Health Services, Gastroenterology & Hepatology
Abstract

Background & aimsNon-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH.MethodsWe analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS).ResultsAmong 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value.ConclusionsThese preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH.Lay summaryLiver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

Published
2019

9. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH

Author

Kimura, Masaki, Iguchi, Takuma, Iwasawa, Kentaro, Dunn, Andrew, Thompson, Wendy L., Yoneyama, Yosuke, Chaturvedi, Praneet, Zorn, Aaron M., Wintzinger, Michelle, Quattrocelli, Mattia, Watanabe-Chailland, Miki, Zhu, Gaohui, Fujimoto, Masanobu, Kumbaji, Meenasri, Kodaka, Asuka, Gindin, Yevgeniy, Chung, Chuhan, Myers, Robert P., Subramanian, G. Mani, Hwa, Vivian, and Takebe, Takanori

Published
2022
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10. Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis

Author

Lawitz, Eric J, Coste, Angie, Poordad, Fred, Alkhouri, Naim, Loo, Nicole, McColgan, Bryan J, Tarrant, Jacqueline M, Nguyen, Tuan, Han, Ling, Chung, Chuhan, Ray, Adrian S, McHutchison, John G, Subramanian, G Mani, Myers, Robert P, Middleton, Michael S, Sirlin, Claude, Loomba, Rohit, Nyangau, Edna, Fitch, Mark, Li, Kelvin, and Hellerstein, Marc

Subjects
Liver Disease, Digestive Diseases, Clinical Research, Biomedical Imaging, Chronic Liver Disease and Cirrhosis, Hepatitis, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Oral and gastrointestinal, Acetyl-CoA Carboxylase, Administration, Oral, Adolescent, Adult, Aged, Elasticity Imaging Techniques, Enzyme Inhibitors, Female, Humans, Isobutyrates, Lipogenesis, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Oxazoles, Prospective Studies, Pyrimidines, Treatment Outcome, Young Adult, TIMP1, ALT, Drug, Clinical Trial, Treatment, Fatty Liver, Clinical Sciences, Gastroenterology & Hepatology
Abstract

Background & aimsIncreased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.MethodsIn an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis.ResultsThe contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF.ConclusionIn an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.

Published
2018

11. GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease

Author

Loomba, Rohit, Kayali, Zeid, Noureddin, Mazen, Ruane, Peter, Lawitz, Eric J, Bennett, Michael, Wang, Lulu, Harting, Eliza, Tarrant, Jacqueline M, McColgan, Bryan J, Chung, Chuhan, Ray, Adrian S, Subramanian, G Mani, Myers, Robert P, Middleton, Michael S, Lai, Michelle, Charlton, Michael, and Harrison, Stephen A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Hepatitis, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Biomedical Imaging, Liver Disease, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Acetyl-CoA Carboxylase, Biomarkers, Carnitine, Double-Blind Method, Elasticity Imaging Techniques, Fatty Liver, Female, Humans, Isobutyrates, Liver Cirrhosis, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Oxazoles, Pyrimidines, De Novo Lipogenesis, Magnetic Resonance Elastography, Tissue Inhibitor of Metalloproteinase 1, Effects, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsDe novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH.MethodsWe analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy.ResultsA relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976.ConclusionsIn a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

Published
2018

12. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

Author

Loomba, Rohit, Lawitz, Eric, Mantry, Parvez S, Jayakumar, Saumya, Caldwell, Stephen H, Arnold, Hays, Diehl, Anna Mae, Djedjos, C Stephen, Han, Ling, Myers, Robert P, Subramanian, G Mani, McHutchison, John G, Goodman, Zachary D, Afdhal, Nezam H, Charlton, Michael R, and Investigators, for the GS‐US‐384‐1497

Subjects
Clinical Trials and Supportive Activities, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, Hepatitis, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Oral and gastrointestinal, Antibodies, Monoclonal, Humanized, Benzamides, Elasticity Imaging Techniques, Female, Humans, Imidazoles, Liver Cirrhosis, MAP Kinase Kinase Kinase 5, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Protein Kinase Inhibitors, Pyridines, GS-US-384-1497 Investigators, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology
Abstract

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).

Published
2018

13. DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis

Author

Loomba, Rohit, Gindin, Yevgeniy, Jiang, Zhaoshi, Lawitz, Eric, Caldwell, Stephen, Djedjos, C Stephen, Xu, Ren, Chung, Chuhan, Myers, Robert P, Subramanian, G Mani, Goodman, Zachary, Charlton, Michael, Afdhal, Nezam H, and Diehl, Anna Mae

Subjects
Liver Disease, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Aging, Genetics, Human Genome, Clinical Research, Hepatitis, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Aged, Aging, Premature, Biomarkers, Biopsy, Case-Control Studies, Clinical Trials, Phase II as Topic, Collagen, CpG Islands, DNA Methylation, Datasets as Topic, Epigenesis, Genetic, Female, Fibrosis, Humans, Liver, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Randomized Controlled Trials as Topic, Severity of Illness Index, Hepatology
Abstract

A DNA methylation (DNAm) signature (the "Horvath clock") has been proposed as a measure of human chronological and biological age. We determined peripheral blood DNAm in patients with nonalcoholic steatohepatitis (NASH) and assessed whether accelerated aging occurs in these patients. DNAm signatures were obtained in patients with biopsy-proven NASH and stage 2-3 fibrosis. The DNAm profile from one test and two validation cohorts served as controls. Age acceleration was calculated as the difference between DNAm age and the predicted age based on the linear model derived from controls. Hepatic collagen content was assessed by quantitative morphometry. The Horvath clock accurately predicts the chronological age of the entire cohort. Age acceleration was observed among NASH subjects compared with control data sets and our test controls. Age acceleration in NASH subjects did not differ by fibrosis stage but correlated with hepatic collagen content. A set of 152 differentially methylated CpG islands between NASH subjects and controls identified gene set enrichment for transcription factors and developmental pathways. Patients with NASH exhibit epigenetic age acceleration that correlates with hepatic collagen content.

Published
2018

16. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials

Author

Gadano, Adrian, Martins, Marcelo, Angus, Peter, Bate, John, Danta, Mark, George, Jacob, Hodge, Alexander, Kontorinis, Nickolas, Roberts, Stuart, Sanagapalli, Santosh, Skoien, Richard, Thompson, Alexander, Zekry, Amany, Stauber, Rudolf, Trauner, Michael, Moreno, Christophe, Reynaert, Hendrik, Verbeke, Len, Silva, Mario Reis Alvares da, Parise, Edison, Oliveira, Claudia Pinto Marques Souza de, Araujo, Roberta Chaves, Martinelli, Ana de Lourdes Candolo, Borman, Meredith, Chandok, Natasha, Elkhashab, Magdy, Fraser, Hughie, Kaita, Kelly, Ma, Mang, Marotta, Paul, Ramji, Alnoor, Tam, Edward, Yoshida, Eric, Swain, Mark, Sebastiani, Giada, Petrunia, Denis, Abergel, Armando, Anty, Rodolphe, Bourlière, Marc, Boursier, Jérôme, Bureau, Christophe, Castera, Laurent, Habersetzer, François, Hézode, Christophe, Ledinghen, Victor De, Leroy, Vincent, Loustaud-Ratti, Véronique, Mathurin, Philippe, Pol, Stanislas, Zoulim, Fabien, Hinrichsen, Holger, Ingiliz, Patrick, Lammert, Frank, Manns, Michael, Schattenberg, Jörn, Schiefke, Ingolf, Trautwein, Christian, Zeuzem, Stefan, Hui, Aric, Li, King-Kong, Wong, Vincent, Acharya, Subrat, Chowdhury, Abhijit, Duseja, Ajay, Kapoor, Dharmesh, Mukewar, Shrikant, Sarin, Shiv, Shah, Samir, Shalimar, Sood, Ajit, Tantry, BV, Ben-Ari, Ziv, Katchman, Helena, Safadi, Rifaat, Veitsman, Ella, Zuckerman, Eli, Brunetto, Maurizia, Lampertico, Pietro, Mangia, Alessandra, Akahane, Takemi, Akuta, Norio, Eguchi, Yuichiro, Fujiyama, Shigetoshi, Genda, Takuya, Hiasa, Yoichi, Ido, Akio, Ikeda, Fusao, Ikegami, Tadashi, Imajo, Kento, Itoh, Yoshito, Iwasa, Motoh, Karino, Yoshiyasu, Kato, Naoya, Kawaguchi, Takumi, Kawanaka, Miwa, Kido, Masahiro, Kobayashi, Tomoo, Kurosaki, Masayuki, Matsuzaki, Yasushi, Mita, Eiji, Mizukoshi, Eishiro, Nakahara, Takashi, Nomura, Hideyuki, Notsumata, Kazuo, Okanoue, Takeshi, Saito, Satoshi, Sakugawa, Hiroshi, Suzuki, Yoshiyuki, Takaguchi, Koichi, Takaki, Akinobu, Takashima, Tomoyuki, Tanaka, Saiyu, Tsuji, Keiji, Ueno, Yoshiyuki, Umemura, Takeji, Uto, Hirofumi, Yamashita, Nobuyuki, Yanase, Mikio, Yatsuhashi, Hiroshi, Yoneda, Masashi, Chan, Wah Kheong, Tan, Soek Siam, Garza, Laura Cisneros, Ladron De Guevara Cetina, Alma, Angeles, Rocio Guadalupe Vargas, Silva, Francisca Martinez, Van Erpecum, Karel, Orr, David, Jabłkowski, Maciej, Jaroszewicz, Jerzy, Ramos, Jose, Ahmed, Taufique, Ang, Tiing, Dan, Yock young, Goh, Boon Bee, Kaliyaperumal, Kalaiyarasi, Yip, Cherng Hann, Baik, Soon Koo, Jang, Byoung Kuk, Jun, Dae Won, Kim, Won, Kim, Hyung Joon, Kim, Ji Hoon, Lee, Kwan Sik, Lee, Chun Kyon, Lim, Young-Suk, Park, Jun Yong, Tak, Won Young, Augustin, Salvador, Perez, Salvador Benlloch, Caballeria, Juan, Luis, Jose, Panero, Calleja, Rodríguez, Jose Carrión, Garcia, Javier Crespo, Samaniego, Javier Garcia, Gibert, Pere Ginès, Prieto, Martin, Gomez, Manuel Romero, Turnes, Juan, Dufour, Jean-Francois, Moriggia, Alberto, Sheen, I-Shyan, Kao, Jia-Horng, Cheng, Pin-Nan, Huang, Jee-Fu, Yang, Sheng-Shun, Su, Wei-Wen, Chen, Chi-Yi, Chien, Rong-Nan, Lo, Gin-Ho, Chu, Chi-Jen, Wang, Horng-Yuan, Hu, Jui-Ting, Huang, Yi Wen, Agarwal, Kosh, Allison, Michael, Anstee, Quentin, Austin, Andrew, Fowell, Andrew, Ch'ng, Chin Lye, Manousou, Pinelopi, Newsome, Philip, Ryder, Stephen, Shankar, Arun, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Alam, Imtiaz, Alba, Laura, Alkhouri, Naim, Allen, Alina, Aqel, Bashar, Balart, Luis, Barritt, A. Sidney, IV, Behari, Jaideep, Bennett, Michael, Bernstein, David, Bhandari, Bal Raj, Bonacini, Maurizio, Borg, Brian, Brown, Kimberly, Bzowej, Natalie, Caldwell, Stephen, Chami, Tawfik, Coates, Allan, Cueli, Adolfo, Davis, Mitchell, deLemos, Andrew, Desai, Archita, Dunn, Winston, Ferreira, Nelson, Fine, Michael, Firpi-Morell, Roberto, Freedland, Curtis, Freilich, Bradley, Fuchs, Michael, Galambos, Michael, Gallegos-Orozco, Juan, Galler, Greg, Ghali, Maged, Ghalib, Reem, Gill, Satinder, Gillis, Marcum, Gilroy, Richard, Gordon, Stuart, Gunn, Nadege, Halegoua-DeMarzio, Dina, Hassan, Mohamed, Hassanein, Tarek, Herring, Robert, Jr., Hong, John, Huang, Jonathan, Kabler, Heidi, Kayali, Zeid, Knapple, Whitfield, Kolli, Geetha, Kowdley, Kris, Krause, Richard, Lawitz, Eric, Lidofsky, Steven, Lim, Joseph, Lipkis, Donald, Loomba, Rohit, Mahgoub, Amar, Malespin, Miguel, Manch, Richard, Mannis, Steven, Manos, Paul, McDonald, Thomas, McKenzie, Mark, Mena, Edward, Merriman, Raphael, Moehlen, Martin William, Montgomery, Richard, Murphy, Robert, Natarajan, Yamini, Neff, Guy, Noureddin, Mazen, Ortiz-Lasanta, Grisell, Pagadala, Mangesh, Patel, Keyur, Patton, Heather, Peyton, Adam, Pimstone, Neville, Poulos, John, Pound, David, Pyrsopoulos, Nikolaos, Rafiq, Nila, Ravendhran, Natarajan, Ravinuthala, Ravi, Reddy, K. Rajendar, Reindollar, Robert, Reynolds, Justin, Rinella, Mary, Rizvi, Syed, Rockey, Don, Rodriguez-Perez, Federico, Ruane, Peter, Rubin, Raymond, Ryan, Michael, Saeian, Kia, Sanyal, Arun, Sarkar, Souvik, Scanga, Andrew, Schiff, Eugene, Schmidt, Warren, Schneider, Jeffrey, Sepe, Thomas, Shah, Dhiren, Shaikh, Obaid, Shankar, Uday, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shiffman, Mitchell, Siddique, Asma, Smith, Matthew, Suarez, Rosa, Talal, Andrew, Te, Helen, Tekola, Bezawit, Tetri, Brent, Thuluvath, Paul, Toro, Doris, Torres, Dawn, Trinh, Huy, Trotter, James, Vento, Angel, Vierling, John, Vuppalanchi, Raj, Waters, Michael, Weisberg, Ilan, Wieland, Amanda, Williams, Alonzo, Younes, Ziad, Adams, Leon, Harding, Damian, Hodge, Alex, Kontorinis, Nick, Strasser, Simone, Thompson, Alex, Horsmans, Yves, Steenkiste, Christophe Van, Bailey, Robert, Giard, Jeanne-Marie, Montano-Loza, Aldo, Puglia, Marco, Tsoi, Keith, Larrey, Dominique, Nguyen-Khac, Eric, Ratziu, Vlad, Spengler, Ulrich, Wiegand, Johannes, Hui, Aric Josun, Acharya, Subrat Kumar, Sarin, Shiv Kumar, Tantry, Vishwanath, Braun, Marius, Hazzan, Rawi, Lurie, Yoav, Colombo, Massimo, Fujii, Hideki, Hashimoto, Etsuko, Kato, Masaki, Ogawa, Koji, Takehara, Tetsuo, Tokushige, Katsutoshi, Garza, Laura Esthela Cisneros, Ladrón De Guevara, Alma Laura, Schultz, Michael, Janczewska, Ewa, Toro, Doris H., Jeong, Sook-Hyang, Kim, Yoon Jun, Lee, Jin-Woo, Ang, Tiing Leong, Bee, George Goh Boon, Benlloch, Salvador, Caballería, Juan, Calleja, José Luis, Rodríguez, Jose A. Carrión, Crespo, Javier, Diago, Moises, Fernandez-Rodriguez, Conrado, García-Samaniego, Javier, Ginès, Pere, Romero, Manuel, Dufour, Jean-François, Alazawi, William, Ch'ng, Chin-Lye, Forton, Daniel, Priest, Matthew, Sheridan, David, Ankoma-Sey, Victor, Balakrishnan, Maya, Bambha, Kiran, Barritt, A. Sidney, Bhandari, Bal, Brandman, Danielle, Chang, Charissa, Corey, Kathleen, Feldman, Michael, Gholam, Pierre, Goff, John, Marzio, Dina Halegoua-De, Harrison, Stephen, Hellstern, Paul, Jr., Herring, Robert, Iyer, Rajalakshmi, Jakiche, Antoine, Kohli, Anita, Krok, Karen, Kugelmas, Marcelo, Kumar, Sonal, Lai, Michelle, Mahmoud, Mitchell, Mantry, Parvez, Marsano, Luis, Nguyen, Tuan, Park, James, Patton, Heather M., Pockros, Paul, Reddy, Rajender, Rodriguez, Miguel, Sarles, Harry, Satapathy, Sanjaya, Sedghi, Shahriar, Shah, Nikunj, Sheikh, Muhammad Yasin, Sigal, Samuel, Stanca, Carmen, Steinbook, Michael, Szabo, Gyongyi, Terrault, Norah, Tong, Myron, Victor, David, Zervos, Xaralambos, Harrison, Stephen A., Wong, Vincent Wai-Sun, Caldwell, Stephen H., Shiffman, Mitchell L., Camargo, Marianne, Li, Georgia, Kersey, Kathryn, Jia, Catherine, Zhu, Yanni, Djedjos, C. Stephen, Subramanian, G. Mani, Myers, Robert P., Anstee, Quentin M., Romero-Gomez, Manuel, Goodman, Zachary, Lawitz, Eric J., and Younossi, Zobair

Published
2020
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17. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study

Author

Lampertico, Pietro, Buti, Maria, Fung, Scott, Ahn, Sang Hoon, Chuang, Wan-Long, Tak, Won Young, Ramji, Alnoor, Chen, Chi-Yi, Tam, Edward, Bae, Ho, Ma, Xiaoli, Flaherty, John F, Gaggar, Anuj, Lau, Audrey, Liu, Yang, Wu, George, Suri, Vithika, Tan, Susanna K, Subramanian, G Mani, Trinh, Huy, Yoon, Seung-Kew, Agarwal, Kosh, Lim, Young-Suk, and Chan, Henry L Y

Published
2020
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21. Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis

Author

Boni, Carolina, Janssen, Harry L.A., Rossi, Marzia, Yoon, Seung Kew, Vecchi, Andrea, Barili, Valeria, Yoshida, Eric M., Trinh, Huy, Rodell, Timothy C., Laccabue, Diletta, Alfieri, Arianna, Brillo, Federica, Fisicaro, Paola, Acerbi, Greta, Pedrazzi, Giuseppe, Andreone, Pietro, Cursaro, Carmela, Margotti, Marzia, Santoro, Rosanna, Piazzolla, Valeria, Brunetto, Maurizia R., Coco, Barbara, Cavallone, Daniela, Zhao, Yang, Joshi, Adarsh, Woo, Jacky, Lau, Audrey H., Gaggar, Anuj, Subramanian, G. Mani, Massetto, Benedetta, Fung, Scott, Ahn, Sang Hoon, Ma, Xiaoli, Mangia, Alessandra, and Ferrari, Carlo

Published
2019
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22. Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Coinfection

Author

Sulkowski, Mark S, Naggie, Susanna, Lalezari, Jacob, Fessel, Walford Jeffrey, Mounzer, Karam, Shuhart, Margaret, Luetkemeyer, Anne F, Asmuth, David, Gaggar, Anuj, Ni, Liyun, Svarovskaia, Evguenia, Brainard, Diana M, Symonds, William T, Subramanian, G Mani, McHutchison, John G, Rodriguez-Torres, Maribel, and Dieterich, Douglas

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Emerging Infectious Diseases, Liver Disease, Clinical Research, Digestive Diseases, Hepatitis - C, Genetics, Clinical Trials and Supportive Activities, HIV/AIDS, Infectious Diseases, Hepatitis, Chronic Liver Disease and Cirrhosis, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Administration, Oral, Adult, Aged, Antiviral Agents, Coinfection, Drug Administration Schedule, Drug Therapy, Combination, Female, Genotype, HIV Infections, Hepacivirus, Hepatitis C, Humans, Male, Middle Aged, RNA, Viral, Ribavirin, Sofosbuvir, Treatment Outcome, Uridine Monophosphate, Viral Load, Young Adult, PHOTON-1 Investigators, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceTreatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon.ObjectiveTo determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment.Design, setting, and participantsOpen-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants.InterventionsTreatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks.Main outcomes and measuresThe primary study outcome was the proportion of patients with SVR (serum HCV

Published
2014

24. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis

Author

Harrison, Stephen A., Abdelmalek, Manal F., Caldwell, Stephen, Shiffman, Mitchell L., Diehl, Anna Mae, Ghalib, Reem, Lawitz, Eric J., Rockey, Don C., Schall, Raul Aguilar, Jia, Catherine, McColgan, Bryan J., McHutchison, John G., Subramanian, G. Mani, Myers, Robert P., Younossi, Zobair, Ratziu, Vlad, Muir, Andrew J., Afdhal, Nezam H., Goodman, Zachary, Bosch, Jaime, and Sanyal, Arun J.

Published
2018
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25. Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and Cirrhosis

Author

Esteban, Rafael, Pineda, Juan A., Calleja, Jose Luis, Casado, Marta, Rodríguez, Manuel, Turnes, Juan, Morano Amado, Luis Enrique, Morillas, Rosa Maria, Forns, Xavier, Pascasio Acevedo, Juan Manuel, Andrade, Raul J., Rivero, Antonio, Carrión, José Antonio, Lens, Sabela, Riveiro-Barciela, Mar, McNabb, Brian, Zhang, Gulan, Camus, Gregory, Stamm, Luisa M., Brainard, Diana M., Subramanian, G. Mani, and Buti, Maria

Published
2018
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26. Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1

Author

Bourlière, Marc, Gordon, Stuart C, Schiff, Eugene R, Tran, Tram T, Ravendhran, Natarajan, Landis, Charles S, Hyland, Robert H, Stamm, Luisa M, Zhang, Jie, Dvory-Sobol, Hadas, Subramanian, G Mani, Brainard, Diana M, McHutchison, John G, Serfaty, Lawrence, Thompson, Alex J, Sepe, Thomas E, Curry, Michael P, Reddy, K Rajender, and Manns, Michael P

Published
2018
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27. TLR7 Agonist Increases Responses of Hepatitis B Virus–Specific T Cells and Natural Killer Cells in Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues

Author

Boni, Carolina, Vecchi, Andrea, Rossi, Marzia, Laccabue, Diletta, Giuberti, Tiziana, Alfieri, Arianna, Lampertico, Pietro, Grossi, Glenda, Facchetti, Floriana, Brunetto, Maurizia R., Coco, Barbara, Cavallone, Daniela, Mangia, Alessandra, Santoro, Rosanna, Piazzolla, Valeria, Lau, Audrey, Gaggar, Anuj, Subramanian, G. Mani, and Ferrari, Carlo

Published
2018
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29. Sofosbuvir–velpatasvir single-tablet regimen administered for 12 weeks in a phase 3 study with minimal monitoring in India

Author

Sood, Ajit, Duseja, Ajay, Kabrawala, Mayank, Amrose, Pradeep, Goswami, Bhadadev, Chowdhury, Abhijit, Sarin, Shiv Kumar, Koshy, Abraham, Hyland, Robert H., Lu, Sophia, Camus, Gregory, Stamm, Luisa M., Brainard, Diana M., Subramanian, G. Mani, Prasad, Madhura, Bhatia, Shobna, Shah, Samir R., Kapoor, Dharmesh, Shalimar, and Saraswat, Vivek

Published
2019
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31. Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy

Author

Jacobson, Ira M., Washington, Mary K., Buti, Maria, Thompson, Alexander, Afdhal, Nezam, Flisiak, Robert, Akarca, Ulus Salih, Tchernev, Konstantin G., Flaherty, John F., Aguilar Schall, Raul, Myers, Robert P., Subramanian, G. Mani, McHutchison, John G., Younossi, Zobair, Marcellin, Patrick, and Patel, Keyur

Published
2017
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32. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials

Author

Jacobson, Ira M., Lawitz, Eric, Gane, Edward J., Willems, Bernard E., Ruane, Peter J., Nahass, Ronald G., Borgia, Sergio M., Shafran, Stephen D., Workowski, Kimberly A., Pearlman, Brian, Hyland, Robert H., Stamm, Luisa M., Svarovskaia, Evguenia, Dvory-Sobol, Hadas, Zhu, Yanni, Subramanian, G. Mani, Brainard, Diana M., McHutchison, John G., Bräu, Norbert, Berg, Thomas, Agarwal, Kosh, Bhandari, Bal Raj, Davis, Mitchell, Feld, Jordan J., Dore, Gregory J., Stedman, Catherine A.M., Thompson, Alexander J., Asselah, Tarik, Roberts, Stuart K., and Foster, Graham R.

Published
2017
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33. The Genome Sequence of the Malaria Mosquito Anopheles gamblae

Author

Holt, Robert A., Subramanian, G. Mani, Halpern, Aaron, Sutton, Granger G., Charlab, Rosane, Nusskern, Deborah R., Wincker, Patrick, Clark, Andrew G., Wides, Ron, Salzberg, Steven L., Loftus, Brendan, Yandell, Mark, Majoros, William H., Rusch, Douglas B., Lai, Zhongwu, Kraft, Cheryl L., Abril, Josep F., Anthouard, Veronique, Arensburger, Peter, Atkinson, Peter W., Baden, Holly, de Berardinis, Veronique, Baldwin, Danita, Benes, Vladimir, Biedler, Jim, Blass, Claudia, Bolanos, Randall, Boscus, Didier, Barnstead, Mary, Cai, Shuang, Chatuverdi, Kabir, Christophides, George K., Chrystal, Mathew A., Clamp, Michele, Cravchik, Anibal, Curwen, Val, Dana, Ali, Delcher, Art, Dew, Ian, Evans, Cheryl A., Flanigan, Michael, Grundschober-Freimoser, Anne, Friedli, Lisa, Gu, Zhiping, Guan, Ping, Guigo, Roderic, Hillenmeyer, Maureen E., Hladun, Susanne L., Hogan, James R., Hong, Young S., Hoover, Jeffrey, Jaillon, Olivier, Ke, Zhaoxi, Kodira, Chinnappa, Kokoza, Elena, Koutsos, Anastasios, Letunic, Ivica, Levitsky, Alex, Liang, Yong, Lin, Jhy-Jhu, Lobo, Neil F., Lopez, John R., Malek, Joel A., McIntosh, Tina C., Meister, Stephan, Miller, Jason, Mobarry, Clark, Mongin, Emmanuel, Murphy, Sean D., O'Brochta, David A., Pfannkoch, Cynthia, Qi, Rong, Regier, Megan A., Remington, Karin, Shao, Hongguang, Sharakhova, Maria V., Sitter, Cynthia D., Shetty, Jyoti, Smith, Thomas J., Strong, Renee, Sun, Jingtao, Thomasova, Dana, Ton, Lucas Q., Topalis, Pantelis, Tu, Zhijian, Unger, Maria F., Walenz, Brian, Wang, Aihui, Wang, Jian, Wang, Mei, Wang, Xuelan, Woodford, Kerry J., Wortman, Jennifer R., Wu, Martin, Yao, Alison, Zdobnov, Evgeny M., Zhang, Hongyu, Zhao, Qi, Zhao, Shaying, Zhu, Shiaoping C., Zhimulev, Igor, Coluzzi, Mario, della Torre, Alessandra, Roth, Charles W., Louis, Christos, Kalush, Francis, Mural, Richard J., Myers, Eugene W., Adams, Mark D., Smith, Hamilton O., Broder, Samuel, Gardner, Malcolm J., Fraser, Claire M., Birney, Ewan, Bork, Peer, Brey, Paul T., Venter, J. Craig, Weissenbach, Jean, Kafatos, Fotis C., Collins, Frank H., and Hoffman, Stephen L.

Published
2002

34. Comparative Genome and Proteome Analysis of Anopheles gambiae and Drosophila melanogaster

Author

Zdobnov, Evgeny M., von Mering, Christian, Letunic, Ivica, Torrents, David, Suyama, Mikita, Copley, Richard R., Christophides, George K., Thomasova, Dana, Holt, Robert A., Subramanian, G. Mani, Mueller, Hans-Michael, Dimopoulos, George, Law, John H., Wells, Michael A., Birney, Ewan, Charlab, Rosane, Halpern, Aaron L., Kokoza, Elena, Kraft, Cheryl L., Lai, Zhongwu, Lewis, Suzanna, Louis, Christos, Barillas-Mury, Carolina, Nusskern, Deborah, Rubin, Gerald M., Salzberg, Steven L., Sutton, Granger G., Topalis, Pantelis, Wides, Ron, Wincker, Patrick, Yandell, Mark, Collins, Frank H., Ribeiro, Jose, Gelbart, William M., Kafatos, Fotis C., and Bork, Peer

Published
2002

35. Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study

Author

Fung, Scott, Kwan, Peter, Fabri, Milotka, Horban, Andrzej, Pelemis, Mijomir, Hann, Hie-Won, Gurel, Selim, Caruntu, Florin A., Flaherty, John F., Massetto, Benedetta, Kim, Kyungpil, Kitrinos, Kathryn M., Subramanian, G. Mani, McHutchison, John G., Yee, Leland J., Elkhashab, Magdy, Berg, Thomas, Sporea, Ioan, Yurdaydin, Cihan, Husa, Petr, Jablkowski, Maciej S., and Gane, Edward

Published
2017
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36. Integration of deep learning-based histopathology and transcriptomics reveals key genes associated with fibrogenesis in patients with advanced NASH

Author

Conway, Jake, primary, Pouryahya, Maryam, additional, Gindin, Yevgeniy, additional, Pan, David Z., additional, Carrasco-Zevallos, Oscar M., additional, Mountain, Victoria, additional, Subramanian, G. Mani, additional, Montalto, Michael C., additional, Resnick, Murray, additional, Beck, Andrew H., additional, Huss, Ryan S., additional, Myers, Robert P., additional, Taylor-Weiner, Amaro, additional, Wapinski, Ilan, additional, and Chung, Chuhan, additional

Published
2023
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37. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

Author

Buti, Maria, Gane, Edward, Seto, Wai Kay, Chan, Henry L Y, Chuang, Wan-Long, Stepanova, Tatjana, Hui, Aric-Josun, Lim, Young-Suk, Mehta, Rajiv, Janssen, Harry L A, Acharya, Subrat K, Flaherty, John F, Massetto, Benedetta, Cathcart, Andrea L, Kim, Kyungpil, Gaggar, Anuj, Subramanian, G Mani, McHutchison, John G, Pan, Calvin Q, Brunetto, Maurizia, Izumi, Namiki, and Marcellin, Patrick

Published
2016
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38. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

Author

Chan, Henry L Y, Fung, Scott, Seto, Wai Kay, Chuang, Wan-Long, Chen, Chi-Yi, Kim, Hyung Joon, Hui, Aric Josun, Janssen, Harry L A, Chowdhury, Abhijit, Tsang, Tak Yin Owen, Mehta, Rajiv, Gane, Edward, Flaherty, John F, Massetto, Benedetta, Gaggar, Anuj, Kitrinos, Kathryn M, Lin, Lanjia, Subramanian, G Mani, McHutchison, John G, Lim, Young-Suk, Acharya, Subrat K, and Agarwal, Kosh

Published
2016
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41. Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B

Author

Marcellin, Patrick, Ahn, Sang Hoon, Ma, Xiaoli, Caruntu, Florin A., Tak, Won Young, Elkashab, Magdy, Chuang, Wan-Long, Lim, Seng-Gee, Tabak, Fehmi, Mehta, Rajiv, Petersen, Joerg, Foster, Graham R., Lou, Lillian, Martins, Eduardo B., Dinh, Phillip, Lin, Lanjia, Corsa, Amoreena, Charuworn, Prista, Subramanian, G. Mani, Reiser, Hans, Reesink, Hendrick W., Fung, Scott, Strasser, Simone I., Trinh, Huy, Buti, Maria, Gaeta, Giovanni B., Hui, Aric J., Papatheodoridis, George, Flisiak, Robert, and Chan, Henry L.Y.

Published
2016
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43. Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens

Author

Wilson, Eleanor M., Kattakuzhy, Sarah, Sidharthan, Sreetha, Sims, Zayani, Tang, Lydia, McLaughlin, Mary, Price, Angie, Nelson, Amy, Silk, Rachel, Gross, Chloe, Akoth, Elizabeth, Mo, Hongmei, Subramanian, G. Mani, Pang, Phillip S., McHutchison, John G., Osinusi, Anu, Masur, Henry, Kohli, Anita, and Kottilil, Shyam

Published
2016

44. Efficacy of Sofosbuvir Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis and Hepatitis C Virus Genotype 2 Infection

Author

Foster, Graham R., Pianko, Stephen, Brown, Ashley, Forton, Daniel, Nahass, Ronald G., George, Jacob, Barnes, Eleanor, Brainard, Diana M., Massetto, Benedetta, Lin, Ming, Han, Bin, McHutchison, John G., Subramanian, G. Mani, Cooper, Curtis, and Agarwal, Kosh

Published
2015
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45. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS)

Author

Bourlière, Marc, Bronowicki, Jean-Pierre, de Ledinghen, Victor, Hézode, Christophe, Zoulim, Fabien, Mathurin, Philippe, Tran, Albert, Larrey, Dominique G, Ratziu, Vlad, Alric, Laurent, Hyland, Robert H, Jiang, Deyuan, Doehle, Brian, Pang, Phillip S, Symonds, William T, Subramanian, G Mani, McHutchison, John G, Marcellin, Patrick, Habersetzer, François, Guyader, Dominique, Grangé, Jean-Didier, Loustaud-Ratti, Véronique, Serfaty, Lawrence, Metivier, Sophie, Leroy, Vincent, Abergel, Armand, and Pol, Stanislas

Published
2015
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46. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study

Author

Kohli, Anita, Osinusi, Anuoluwapo, Sims, Zayani, Nelson, Amy, Meissner, Eric G, Barrett, Lisa L, Bon, Dimitra, Marti, Miriam M, Silk, Rachel, Kotb, Colleen, Gross, Chloe, Jolley, Tim A, Sidharthan, Sreetha, Petersen, Tess, Townsend, Kerry, Egerson, D'Andrea, Kapoor, Rama, Spurlin, Emily, Sneller, Michael, Proschan, Michael, Herrmann, Eva, Kwan, Richard, Teferi, Gebeyehu, Talwani, Rohit, Diaz, Gabbie, Kleiner, David E, Wood, Brad J, Chavez, Jose, Abbott, Stephen, Symonds, William T, Subramanian, G Mani, Pang, Phillip S, McHutchison, John, Polis, Michael A, Fauci, Anthony S, Masur, Henry, and Kottilil, Shyam

Published
2015
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49. Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

Author

Curry, Michael P., Forns, Xavier, Chung, Raymond T., Terrault, Norah A., Brown, Robert, Jr., Fenkel, Jonathan M., Gordon, Fredric, O’Leary, Jacqueline, Kuo, Alexander, Schiano, Thomas, Everson, Gregory, Schiff, Eugene, Befeler, Alex, Gane, Edward, Saab, Sammy, McHutchison, John G., Subramanian, G. Mani, Symonds, William T., Denning, Jill, McNair, Lindsay, Arterburn, Sarah, Svarovskaia, Evguenia, Moonka, Dilip, and Afdhal, Nezam

Published
2015
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