Michael Charlton

Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) and its progressive form non‐alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long‐term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver‐related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long‐term outcomes, and patient‐reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies. Conclusion: Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD. (Hepatology 2018;68:361‐371)

Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis

Nonalcoholic fatty liver disease (NAFLD) is a spectrum comprised of isolated steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and do not carry a significant risk for liver‐related adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high to low prevalence rates is noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition of NASH as an important liver disease, the diagnosis of NASH still requires a liver biopsy that is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, this method suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathological features. A number of noninvasive modalities to diagnose NASH and stage liver fibrosis are being developed. These modalities include predictive models (NAFLD fibrosis score) and serum biomarkers such as enhanced liver fibrosis (ELF). Other tests are based on radiological techniques, such as transient elastography (TE) or magnetic resonance elastography (MRE), which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have area under the curve ranging between 0.76 and 0.90%, with MRE having the best predictive performance. In summary, developing safe and easily accessible noninvasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease, but also to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH. (Hepatology 2018;68:349‐360).

Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Although hepatocellular carcinoma (HCC) is more common in the setting of cirrhosis, there is increasing evidence that it can develop in the setting of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and that steatosis alone can promote carcinogenesis. In addition, obesity, diabetes, and metabolic syndrome are recognized risks for the development of HCC. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. The surveillance for HCC in the setting of noncirrhotic NAFLD/NASH, obesity, diabetes, and metabolic syndrome remains an area of uncertainty.

Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection

BACKGROUND & AIMSnTreatment with direct-acting antiviral (DAA) agents can reduce Model for End-Stage Liver Disease and Child-Pugh-Turcotte (CPT) scores in patients with decompensated cirrhosis caused by hepatitis C virus. However, many of these patients still die or require liver transplantation. We collected data on baseline features of patients and aimed to develop a scoring system to predict response to DAA therapy.nnnMETHODSnWe performed a retrospective analysis of data from 4 trials on the effects of sofosbuvir-based therapy in patients with hepatitis C virus-associated decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). In these trials, patients were given 12 or 24 weeks of treatment with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin. We collected demographic, clinical, treatment response, and laboratory data from patients and tested their associations with patient outcomes at 36 weeks. The primary outcome was factors associated with reduction of CPT score to class A.nnnRESULTSnThe presence of ascites or encephalopathy, serum level of albumin <3.5 g/dL or alanine aminotransferase <60 U/L, and body mass index >25 kg/m2 were associated with an increased risk of not achieving a reduction in CPT to class A, independent of sustained viral response to therapy. Serum level of albumin <2.8 g/dL and abnormal level of bilirubin were associated with an increased risk of liver transplantation or death. We developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated significantly with patient outcomes, which we called the BE3A score. For patients with scores of 4-5, the hazard ratio for reduction of CPT score to class A was 52.3 (95% confidence interval, 15.2-179.7).nnnCONCLUSIONSnWe identified 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated with a reduction of CPT score to class A in patients with hepatitis C virus-associated decompensated cirrhosis receiving DAA therapy. We developed a predictive score using these factors, called the BE3A score, which can be used as a shared decision-making tool, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis.

FGF-19 agonism for NASH: a short study of a long disease

www.thelancet.com Published online March 5, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30425-2 1 Non-alcoholic steatohepatitis (NASH) has emerged as the most common cause of liver disease worldwide and is on a trajectory to become the most common indication for liver transplantation. Interest in developing effective therapies for NASH has been proportional. Since its original scientific description, NASH has been a histologically defined disease, characterised by hepatic steatosis and inflammation with variable presence and severity of Mallory’s hyaline, balloon degeneration, and, most important clinically, fibrosis. Steatosis and inflammation, and thereby fibrosis, are thought to be causally related through hepatic lipotoxicity. Many of the therapeutic agents currently in development for NASH, such as the agonists of the endocrine fibroblast growth factor (FGF) family (FGF-19 and FGF-21), have hepatic delipidation as a primary mechanism of intended effect. The pleiotropic effects of FGF-19, including inhibition of bile acid synthesis from cholesterol via cytochrome P450 7A1, and inhibition of insulin-induced hepatic lipogenesis, make FGF-19 agonism an attractive potential therapeutic mechanism. It is thus with great interest that the field has awaited the results of the phase 2A, 12 week, randomised, double-blind, placebo-controlled study assessing the efficacy and safety of NGM282, a recombinant FGF-19 agonist, reported in The Lancet by Stephen Harrison and colleagues. Study size was modest (n=82). At 12 weeks, 20 (74%) of 27 patients who received 3 mg NGM282 and 22 (79%) of 28 patients who received 6 mg NGM282 met the primary endpoint of a 5% or more decrease in absolute liver fat content, compared with two (7%) of 27 patients in the placebo group. A substantial proportion of patients (seven [26%] in the 3 mg dose group, 11 [39%] in the 6 mg dose group, and none in the placebo group) normalised liver fat content. The differences in liver fat content between study groups were highly significant. NGM282 also significantly reduced serum aminotransferase concentrations, with decreases in aminotransferases correlating with changes in liver fat content. The speed and magnitude of hepatic delipidation achieved in the treatment groups are unequivocally impressive, setting a new efficacy benchmark for pharmacotherapy of these aspects of NASH. The concomitant and correlative changes in a broad array of biomarkers of inflammation and fibrosis are also encouraging. These exciting results notwithstanding, there are some important considerations in interpreting the results of this phase 2 trial. The first is the side-effect profile of NGM282, with three (11%) patients in the 3 mg dose group and three (11%) in the 6 mg group requiring early discontinuation of study drug (vs none in the placebo group). More patients experienced a grade 2 or 3 adverse event than normalised liver fat content. Adverse events were mostly gastrointestinal in nature, including high frequencies of diarrhoea, abdominal pain, and nausea. One patient in the 3 mg dose group experienced pancreatitis. FGF-19 agonism has diverse gastrointestinal effects, including altered intestinal motility, believed to be mediated in part by FGF-19 inhibition of bile acid synthesis. Bile acid synthesis, as measured by C4 (7αhydroxy-4-cholesten-3-one) activity, was attenuated by 80–90% in the NGM282 groups, with the degree of attenuation correlating with decrease in liver fat content. The significant increases in cholesterol and LDL cholesterol (LDL-C) recorded in the NGM282 groups are also worthy of consideration. While the reported effect of large versus small particle LDL-C on risk of cardiovascular mortality and events is variable, the potential for increased risk of cardiovascular disease with FGF-19-induced dyslipidaemia will be an important consideration as cardiovascular disease is a much more common cause of mortality in patients with NASH than liver disease. Finally, NASH is most commonly a hepatic manifestation of obesity and metabolic syndrome, both chronic conditions. Liver-related clinical events occur in a minority of patients with NASH in whom fibrosis had progressed to cirrhosis over decades. In this context, 12 weeks, while enough to show lowering of liver fat content, is a physiological blink of an eye. Studies of much longer duration that show a clinically relevant sustained benefit of treatment (transaminase concentrations returned toward baseline 4 weeks after cessation of treatment with NGM282), net of adverse events, are clearly needed. The adverse event profile and physiological effects (eg, of diminished bile acid pool) associated with NGM282 suggest longer periods FGF-19 agonism for NASH: a short study of a long disease

Class III obesity is a risk factor for the development of acute-on-chronic liver failure in patients with decompensated cirrhosis

BACKGROUND & AIMSnAcute-on-chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes patients with decompensated cirrhosis to the development of ACLF.nnnMETHODSnWe examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (body mass index [BMI] <30), obese class I-II (BMI 30-39.9) and obese class III (BMI ≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence.nnnRESULTSnAmong 387,884 patient records of decompensated cirrhosis, 116,704 (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (hazard ratio 1.24; 95% CI 1.09-1.41; pu202f<0.001). This finding was confirmed using the NIS (odds ratio 1.30; 95% CI 1.25-1.35; pu202f<0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had a greater prevalence of renal failure.nnnCONCLUSIONnClass III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly high prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF.nnnLAY SUMMARYnIn this study, we identify that among patients with decompensated cirrhosis, class III obesity (severe/morbid obesity) is a modifiable risk factor for the development of acute-on-chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent in obese patients, particularly those with class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure.

GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients with Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMSnDe 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.nnnMETHODSnWe 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.nnnRESULTSnA relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (Pxa0= .004 vs placebo), 23% given GS-0976 5 mg (Pxa0= .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%; Pxa0= .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 20xa0mg. 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% andxa013% in serum levels of triglycerides were observed in patients given GS-0976.nnnCONCLUSIONSnIn 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.

International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients

Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.

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

BACKGROUND & AIMSnNon-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.nnnMETHODSnWe 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).nnnRESULTSnAmong 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24u202fweeks 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.nnnCONCLUSIONSnThese preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH.nnnLAY SUMMARYnLiver 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.