Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial.

BACKGROUND AND AIMS: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). APPROACH AND RESULTS: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). CONCLUSIONS: Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

Comparison of transarterial chemoembolization in patients with unresectable, diffuse vs focal hepatocellular carcinoma.

HYPOTHESIS: Transarterial chemoembolization (TACE) is beneficial for selected patients with unresectable hepatocellular carcinoma (HCC). DESIGN AND SETTING: A prospective comparison study in a tertiary hospital. STUDY PERIOD: November 21, 1995, to May 2, 2001, with a mean follow-up of 939 days. PATIENTS: A total of 157 TACE treatments were performed in 88 patients with unresectable HCC: 132 treatments in 69 patients with focal HCC (F-HCC) and 25 treatments in 19 patients with diffuse HCC (D-HCC). INTERVENTIONS: Transarterial chemoembolization consisted of selective catheterization and intra-arterial infusion of a mixture of doxorubicin hydrochloride, cisplatin, and mitomycin followed by embolization. Sequential treatments were performed for bilobar HCC. MAIN OUTCOME MEASURES: Child-Pugh classification and clinical outcomes, including alpha-fetoprotein (AFP) response, length of hospital stay, readmission rate, and survival, were compared between patients with F-HCC and D-HCC following TACE using the chi(2) test, Fisher exact test, or t test (2-tailed, unpaired). RESULTS: Fifty-eight patients (84%) in the F-HCC group and 18 patients (95%) in the D-HCC group had cirrhosis. For those patients with cirrhosis, 58 (100%) in the F-HCC group and 14 (78%) in the D-HCC group had a Child-Pugh score of A or B (P =.002). The mean baseline AFP was higher in the D-HCC group: 55 577 vs 7815 ng/mL in the F-HCC group (P =.001). Of the patients secreting AFP, 4 (29%) of 14 in the D-HCC group and 30 (68%) of 44 in the F-HCC group had a significant decrease in AFP 1 month following TACE (P =.01). The mean hospital stay was longer (3 vs 1.9 days; P =.001), and readmissions occurred more frequently (44% vs 9%; P<.001) in the D-HCC group. The mean survival rate was significantly higher in the F-HCC group: 425 vs 103 days (P<.001). CONCLUSIONS: In patients with F-HCC, TACE is well tolerated and provides a survival benefit. However, there is no apparent benefit for patients with D-HCC. Importantly, tumor characteristics and hepatic reserve are essential criteria for successful TACE.

Primary prevention of cirrhosis. Public health strategies that can make a difference.

Cirrhosis is associated with high morbidity and mortality and often affects persons during the most productive years of life. In the United States, alcoholic liver disease is the leading contributor to the overall prevalence of cirrhosis, followed by infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). In this article, Drs Karsan, Rojter, and Saab examine lifestyle behaviors that can lead to cirrhosis and enumerate public health strategies aimed at primary prevention.

Is it cost-effective to treat recurrent hepatitis C infection in orthotopic liver transplantation patients?

Hepatitis C virus (HCV) recurs in the allograft almost universally after orthotopic liver transplantation (OLT), with a variable course ranging from mild hepatitis to frank cirrhosis. The uncertain prognosis after OLT has lead to widely increased use of antiviral therapy in the post-OLT setting. We compared two scenarios (antiviral therapy versus no antiviral therapy) using a Markov-based decision analytic model to simulate costs and health outcomes for recurrent HCV in three age and sex cohorts of post-OLT patients. Efficacy outcomes included total costs, cases of cirrhosis prevented, cases of death prevented, life-years gained, and cost per life-year saved. One-way sensitivity analyses were performed for sustained viral response; annual drug cost, discount rate, compliance, cirrhosis rate, decompensation rate, and cost of dying. Two-way sensitivity analyses were performed to compare effects of (1) changing sustained viral response and antiviral therapy costs, and (2) changing the sustained viral response and cirrhosis rate. The incremental cost-effectiveness ratio for the reference patient cohort of 1,000 men aged 55 years was $29,100 per life-year saved. The model was sensitive to drug costs, cirrhosis rate, and sustained viral response. The two-way sensitivity analysis showed that antiviral therapy remained cost-effective even if drug costs increased, as long as these increases were associated with higher sustained viral responses. The cost-effectiveness ratio also was sensitive to age and sex of cohort. The decision to treat HCV after OLT with antiviral therapy usually is based on many considerations. Such treatment can be cost-effective if baseline assumptions are met. Our model was sensitive to antiviral drug costs, cirrhosis rate, and sustained viral response. Patients with a progressive course of recurrent HCV are likely to have the greatest gain from antiviral therapy.