Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Utility of pathologist panels for achieving consensus in NASH histologic scoring in clinical trials: Data from a phase 3 study.

BACKGROUND: Liver histopathologic assessment is the accepted surrogate endpoint in NASH trials; however, the scoring of NASH Clinical Research Network (CRN) histologic parameters is limited by intraobserver and interobserver variability. We designed a consensus panel approach to minimize variability when using this scoring system. We assessed agreement between readers, estimated linear weighted kappas between 2 panels, compared them with published pairwise kappa estimates, and addressed how agreement or disagreement might impact the precision and validity of the surrogate efficacy endpoint in NASH trials. METHODS: Two panels, each comprising 3 liver fellowship-trained pathologists who underwent NASH histology training, independently evaluated scanned whole slide images, scoring fibrosis, inflammation, hepatocyte ballooning, and steatosis from baseline and month 18 biopsies for 100 patients from the precirrhotic NASH study REGENERATE. The consensus score for each parameter was defined as agreement by ≥2 pathologists. If consensus was not reached, all 3 pathologists read the slide jointly to achieve a consensus score. RESULTS: Between the 2 panels, the consensus was 97%-99% for steatosis, 91%-93% for fibrosis, 88%-92% for hepatocyte ballooning, and 84%-91% for inflammation. Linear weighted kappa scores between panels were similar to published NASH CRN values. CONCLUSIONS: A panel of 3 trained pathologists independently scoring 4 NASH CRN histology parameters produced high consensus rates. Interpanel kappa values were comparable to NASH CRN metrics, supporting the accuracy and reproducibility of this method. The high concordance for fibrosis scoring was reassuring, as fibrosis is predictive of liver-specific outcomes and all-cause mortality.

Nonalcoholic fatty liver disease among HIV-infected persons.

OBJECTIVE: To describe the prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) among HIV-infected persons not infected with hepatitis C virus (HCV). DESIGN: : A cross-sectional study among HIV-infected patients in a large HIV clinic. METHODS: NAFLD was defined as steatosis among patients without viral hepatitis (B or C) coinfection or excessive alcohol use. The prevalence of NAFLD was identified by ultrasound examination evaluated by 2 radiologists blinded to the clinic information; liver biopsies were performed on a subset of the study population. Factors associated with NAFLD were evaluated by proportional odds logistic regression models. RESULTS: Sixty-seven of 216 patients (31%) had NAFLD based on ultrasound evaluation. Among those with NAFLD, steatosis was graded as mild in 60%, moderate in 28%, and severe/marked in 12%. Factors associated with the degree of steatosis on ultrasound examination in the multivariate model included increased waist circumference [odds ratio (OR) 2.1 per 10 cm, P < 0.001], elevated triglyceride levels (OR 1.2 per 100 mg/dL, P = 0.03), and lower high-density lipoprotein levels (OR 0.7, per 10 mg/dL, P = 0.03). African Americans were less likely to have NAFLD compared with whites (14% vs. 35%), although this did not reach statistical significance (OR 0.4, P = 0.08). Similar associations were noted for the subset of patients diagnosed by liver biopsy. CD4 cell count, HIV viral load, duration of HIV infection, and antiretroviral medications were not independent risk factors associated with NAFLD after adjustment for dyslipidemia or waist circumference. CONCLUSIONS: NAFLD was common among this cohort of HIV-infected HCV-seronegative patients. NAFLD was associated with a greater waist circumference, low high-density lipoprotein, and high triglyceride levels. Antiretroviral medications were not associated with NAFLD; prospective studies are needed to confirm this finding.

Helminthic Infections of the Liver.

Human helminthic infestation is exceedingly common on a global scale, with as many as 1.5 to 2 billion people affected worldwide. Helminths (parasitic worms) that infect the liver and hepatobiliary system include nematodes (roundworms), cestodes (tapeworms), and trematodes (flatworms or flukes). The majority of morbidity and mortality from these infestations is caused by the host immune response to the larvae or adult worm. Helminthic disease manifestations vary from the extremes of asymptomatic carriage to cirrhosis and decompensated liver disease. Current basic science and clinical research focus on improvements in medical therapy, mass screening and chemoprophylaxis, and the development of preventative vaccine strategies.

Helminthic infections of the liver.

Human helminthic infestation is exceedingly common on a global scale, with as many as 1.5 to 2 billion people affected worldwide. Helminths (parasitic worms) that infect the liver and hepatobiliary system include nematodes (roundworms), cestodes (tapeworms), and trematodes (flatworms or flukes). The majority of morbidity and mortality from these infestations is caused by the host immune response to the larvae or adult worm. Helminthic disease manifestations vary from the extremes of asymptomatic carriage to cirrhosis and decompensated liver disease. Current basic science and clinical research focus on improvements in medical therapy, mass screening and chemoprophylaxis, and the development of preventative vaccine strategies.