Insulin-like growth factor-I (IGF-I) in human hepatoma cells (HEP-G2) has, in addition to its effect on cell growth, shortterm metabolic effects acting through its own receptor. We have demonstrated that normal human hepatocytes, compared with HEP-G2 cells, have virtually no IGF-I binding sites. Because the rate of growth is the major difference between the hepatoma and the normal liver, we asked if normal liver might express IGF-I binding sites under physiologic growth conditions. Indeed, whereas adult rat hepatocytes have low IGF-I binding sites similar to those in human liver, hepatocytes from regenerating liver after 3 d subtotal hepatectomy have an approximately sixfold increase (P < 0.005) and those from fetal rat liver a -12-fold increase (P < 0.005), to levels comparable to those in the HEP-G2 cells. The specificity of 125I IGF-I binding to its receptor was demonstrated by competition studies with monoclonal antibodies directed toward the IGF-I and the insulin receptors, with unlabeled IGF-I and insulin and by affinity labeling experiments. Thus, if IGF-I has any shortterm metabolic functions in the adult human liver, it is not through interaction with its own receptor. Autocrine regulation by IGF-I of liver growth appears possible since IGF-I binding sites are expressed under pathological and physiological conditions of growth. The mechanism that couples these two phenomena remains to be elucidated.

Background and Aims Advanced fibrosis attributable to NASH is a leading cause of end‐stage liver disease. Approach and Results In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3‐F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two‐drug combinations, once‐daily for 48 weeks. The primary endpoint was a ≥1‐stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo‐treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3‐F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2‐point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin‐18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%‐29% of cilofexor versus 15% of placebo‐treated patients. Conclusions In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer‐term therapy in patients with advanced fibrosis attributable to NASH.

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion: A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (Hepatology 2016;63:437–444)

In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis. ClinicalTrials.gov ID: NCT02378961.

It has been suggested that lipid peroxidation plays an important role in hepatic fibrogenesis resulting from chronic iron overload. Vitamin E is an important lipid-soluble antioxidant that has been shown to be decreased in patients with hereditary hemochromatosis and in experimental iron overload. The aim of this study was to determine the effects of vitamin E supplementation on hepatic lipid peroxidation and fibrogenesis in an animal model of chronic iron overload. Rats were fed the following diets for 4, 8, or 14 mo: standard laboratory diet (control), diet with supplemental vitamin E (200 IU/kg, control + E), diet with carbonyl iron (Fe), and diet with carbonyl iron supplemented with vitamin E (200 IU/kg. Fe + E). Iron loading resulted in significant decreases in hepatic and plasma vitamin E levels at all time points, which were overcome by vitamin E supplementation. Thiobarbituric acid-reactive substances (an index of lipid peroxidation) were increased three- to fivefold in the iron-loaded livers; supplementation with vitamin E reduced these levels by at least 50% at all time points. Hepatic hydroxyproline levels were increased twofold by iron loading. Vitamin E did not affect hydroxyproline content at 4 or 8 mo but caused an 18% reduction at 14 mo in iron-loaded livers. At 8 and 14 mo, vitamin E decreased the number of alpha-smooth muscle actin-positive stellate cells in iron-loaded livers. These results demonstrate a dissociation between lipid peroxidation and collagen production and suggest that the profibrogenic action of iron in this model is mediated through effects which cannot be completely suppressed by vitamin E.