Hepatology : official journal of the American Association for the Study of Liver Diseases
-
Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8(+) T-lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand-1 and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia-induced up-regulation of stromal cell-derived 1 alpha. Inhibition of the stromal cell-derived 1 alpha receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8(+) T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand-1 receptor programmed death receptor-1 (PD-1) showed antitumor effects in treatment-naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. ⋯ Anti-PD-1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti-PD-1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors.
-
Randomized Controlled Trial
Randomized trial of interferon- and ribavirin-free ombitasvir/paritaprevir/ritonavir in treatment-experienced hepatitis C virus-infected patients.
Approximately 2 million Japanese individuals are infected with hepatitis C virus and are at risk for cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Patients in whom interferon (IFN)/ribavirin (RBV) therapy has failed remain at risk as effective therapeutic options are limited. This phase 2, randomized, open-label study evaluated an IFN- and RBV-free regimen of once-daily ombitasvir (ABT-267), an NS5A inhibitor, plus paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (paritaprevir/ritonavir), in pegylated IFN/RBV treatment-experienced Japanese patients with hepatitis C virus subtype 1b or genotype 2 infection. Patients without cirrhosis (aged 18-75 years) with subtype 1b infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 or 24 weeks; patients with genotype 2 infection received ombitasvir 25 mg plus paritaprevir/ritonavir 100/100 mg or 150/100 mg for 12 weeks. Sustained virologic response (SVR) at posttreatment week 24 (SVR24 ) was the primary endpoint. Adverse events were collected throughout the study. One hundred ten patients received ≥1 dose of study medication. In the subtype 1b cohort, SVR24 rates were high (88.9%-100%) regardless of paritaprevir dose or treatment duration. In the genotype 2 cohort, SVR24 rates were 57.9% and 72.2% with 100 mg and 150 mg of paritaprevir, respectively. The SVR24 rate was higher in patients with subtype 2a (90%) than 2b (27%). Concordance between SVR12 and SVR24 was 100%. The most common adverse events overall were nasopharyngitis (29%) and headache (14%). ⋯ In this difficult-to-treat population of patients in whom prior pegylated IFN/RBV had failed, ombitasvir/paritaprevir/ritonavir demonstrated potent antiviral activity with a favorable safety profile among Japanese patients with hepatitis C virus genotype 1b or 2a infection.
-
Randomized Controlled Trial
Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). ⋯ Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.
-
Transcatheter arterial chemoembolization (TACE) is the first-line therapy recommended for patients with intermediate hepatocellular carcinoma (HCC). However, in clinical practice, these patients are often referred to surgical teams to be evaluated for hepatectomy. After making a treatment decision (e.g., TACE or surgery), physicians may discover that the alternative treatment would have been preferable, which may bring a sense of regret. Under this premise, it is postulated that the optimal decision will be the one associated with the least amount of regret. Regret-based decision curve analysis (Regret-DCA) was performed on a Cox's regression model developed on 247 patients with cirrhosis resected for intermediate HCC. Physician preferences on surgery versus TACE were elicited in terms of regret; threshold probabilities (Pt) were calculated to identify the probability of survival for which physicians are uncertain of whether or not to perform a surgery. A survey among surgeons and hepatologists regarding three hypothetical clinical cases of intermediate HCC was performed to assess treatment preference domains. The 3- and 5-year overall survival rates after hepatectomy were 48.7% and 33.8%, respectively. Child-Pugh score, tumor number, and esophageal varices were independent predictors of survival (P<0.05). Regret-DCA showed that for physicians with Pt values of 3-year survival between 35% and 70%, the optimal strategy is to rely on the prediction model; for physicians with Pt<35%, surgery should be offered to all patients; and for Pt values>70%, the least regretful strategy is to perform TACE on all patients. The survey showed a significant separation among physicians' preferences, indicating that surgeons and hepatologists can uniformly act according to the regret threshold model. ⋯ Regret theory provides a new perspective for treatment-related decisions applicable to the setting of intermediate HCC.
-
Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment-experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78-100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. ⋯ In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified.