Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation (LT). The rate of HCV infection is high in patients on ...hemodialysis and in patients infected with human immunodeficiency virus (HIV). In liver transplant patients with HCV infection, recurrent HCV infection of the transplanted liver is universal and results in rapid liver fibrosis progression. In patients with HCV/HIV coinfection as well, liver fibrosis advances rapidly. Thus, there is an urgent need for prompt HCV infection treatment in these special populations (i.e. HIV/HCV coinfection, HCV infection after LT, and dialysis patients). Interferon (IFN)‐based therapy for HCV infection could not achieve a high rate of sustained viral response and could cause severe adverse events in the aforementioned special populations. Direct‐acting antivirals (DAAs) have recently been developed, and clinical trials have shown that IFN‐free DAA‐based therapies are associated with a significantly better safety and therapeutic profile than IFN‐based therapies. However, the majority of the initial DAA trials excluded special populations; thus, the efficacy and safety of IFN‐free DAA‐based therapy in special populations remained to be clearly established. Although recent clinical trials and clinical studies have shown the high efficacy and safety of this therapy even in special populations, several unresolved problems, including emergence of resistance‐associated variants after failure to respond to DAAs and HCC occurrence after DAA therapy, still exist. Hence, in this review, we discuss the recent advances in anti‐HCV therapy for special populations and the remaining problems regarding this therapy.
Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is high and is moreover associated ...with a poor prognosis. In liver transplantation patients with HCV infection, recurrent HCV infection is universal, and re-infected HCV causes rapid progression of liver fibrosis and graft loss. Additionally, in patients with HCV and human immunodeficiency virus (HIV) co-infection, liver fibrosis progresses rapidly. Thus, there is an acute need for prompt treatment of HCV infection in these special populations (i.e., hemodialysis, liver transplantation, HIV co-infection). However, until recently, the standard anti-HCV treatment involved the use of interferon-based therapy. In these special populations, interferon-based therapies could not achieve a high rate of sustained viral response and moreover were associated with a higher rate of adverse events. With the development of novel direct-acting antivirals (DAAs), the landscape of anti-HCV therapy for special populations has changed dramatically. Indeed, in special populations treated with interferon-free DAAs, the sustained viral response rate was above 90%, with a lower incidence and severity of adverse events.
Background
Entecavir and tenofovir–disoproxil–fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can ...impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism.
Methods
A retrospective study was performed on HBV patients administered entecavir or tenofovir–disoproxil–fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6–12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir–disoproxil–fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism.
Results
Administration of tenofovir–disoproxil–fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir–disoproxil–fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir–disoproxil–fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir–disoproxil–fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including
CPT1
and
CD36
. Alternatively, silencing of PPAR-α reversed the effects of tenofovir–disoproxil–fumarate on CD36.
Conclusions
Tenofovir–disoproxil–fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.
Background
Decompensated liver cirrhosis patients with refractory ascites or pleural effusion have a poor prognosis. Tolvaptan has been used for treating water retention associated with cirrhosis. ...However, despite the short-term response, water retention recurrence is still observed in some cases. This study aimed to clarify the water retention recurrence rate and the relationship between long-term response without recurrence and prognosis.
Methods
Altogether, 100 patients with decompensated cirrhosis treated with tolvaptan were retrospectively analyzed. Recurrence was evaluated according to the criteria of the EASL clinical practice guideline. The recurrence rate and prognosis of non-responders, patients with recurrence, and long-term responders were analyzed. The baseline factors related to short-term response, recurrence, and long-term response were also evaluated.
Results
Approximately 31.0% of the short-term responders had recurrence. Although there was no significant difference in the prognosis by short-term response (
p
= 0.07), the long-term responders had a significantly better prognosis than those with recurrence and non-responders (
p
< 0.01). Low CRP levels and high urinary Na/K ratios were significant factors related to short-term response, and the presence of acute kidney injury was also a factor related to non-response. The low CRP level (relapse: < 1.10 mg/dl, long-term response: < 0.94 mg/dl) was identified as a factor related to recurrence and long-term response.
Conclusion
The long-term responders without recurrence had a significantly better prognosis. CRP was a useful predictor for long-term response, whereas renal function parameters were useful predictors for short-term response. Inflammation control may be important for long-term response and prognosis in cirrhosis patients with water retention.
Liver stiffness measurement (LSM) is a useful tool for assessing advanced liver fibrosis, an important risk factor for hepatocellular carcinoma (HCC) following hepatitis C (HCV) eradication. This ...study aimed to clarify the non-invasive factors associated with HCC following sustained virological response (SVR) and to identify the low-risk group. 567 patients without history of HCC who achieved SVR at 24 weeks (SVR24) after IFN-free treatment were retrospectively analyzed. The cumulative incidence of HCC and the risk factors were examined using pre-treatment and SVR24 data. The median observation period was 50.2 months. Thirty cases of HCC were observed, and the 4-year cumulative incidence of HCC was 5.9%. In multivariate analysis, significant pre-treatment factors were age ≥ 71 years (hazard ratio HR: 3.402) and LSM ≥ 9.2 kPa (HR: 6.328); SVR24 factors were age ≥ 71 years (HR: 2.689) and LSM ≥ 8.4 kPa (HR: 6.642). In cases with age < 71 years and LSM < 8.4 kPa at the time of SVR24, the 4-year cumulative incidence of HCC was as low as 1.1%. Both pre-treatment LSM (≥ 9.2 kPa) and SVR24 LSM (≥ 8.4 kPa) and age (≥ 71 years) are useful in predicting the risk of HCC after SVR with IFN-free treatment. Identification of low-risk individuals may improve the efficiency of follow-up.
Background. There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. ...Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. Methods. NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15 μg/kg) and at week 3 in rats with liver fibrosis (20 μg/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated in vitro. Results. AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (Tnf-) α, interleukin- (Il-) 1β and Il-6, and transforming growth factor- (Tgf-) β. Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. In vitro, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway. Conclusions. AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.
A recent study showed that a cocktail of three small molecules, Y-27632, A83-01, and CHIR99021 (YAC), converts mature hepatocytes (MHs) into proliferative bipotent cells that can be induced into MHs ...and cholangiocytes in rats. However, when we reproduced these experiments, it was found that bipotent cells may be derived from resident liver progenitor cells (LPCs), whose proliferative activity was promoted by YAC. A simple and efficient sorting scheme was also developed in this study to harvest high-purity and high-yield LPCs. The inducible bipotency of purified LPCs was verified; in addition, they were found to spontaneously differentiate into hepatocytes and cholangiocytes due to changes in proliferative status even without induction. Moreover, during the differentiation process, some hepatocytes spontaneously reconverted to LPCs under certain conditions, such as the release of contact inhibition. These findings may improve our understanding of LPCs and provide a cell source for regenerative medicine.
•
A small-molecule cocktail promotes rat liver progenitor proliferation
in vitro
•
Highly purified progenitors can be simply obtained by their physical properties
•
Purified progenitors preferentially proliferate and then spontaneously differentiate
•
Progenitor differentiation is closely related to varied proliferation signals
In this article, Ohnishi and colleagues showed that a small-molecule cocktail promotes the proliferation of rat liver progenitor cells. They also developed a simple and effective approach to obtain a large number of highly purified liver progenitor cells. At the same time, they revealed how progenitor cells spontaneously coordinate their proliferation and differentiation
in vitro
.
Hepatitis B virus (HBV) infection is a globally distributed health problem. The number of carriers of HBV is estimated to exceed 240 million people worldwide. Compared with uninfected individuals, ...HBV carriers have an increased risk of developing hepatocellular carcinoma. The prevention of HBV infection is therefore strongly recommended, and a HBV vaccine is available. For carriers, treatment with nucleoside/nucleotide reverse transcriptase inhibitors is available, but infection frequently requires chronic treatment via a lifetime of medication. Thus, curing HBV infection remains a major challenge. However, despite the development of an infectious HBV cell culture system and recent intense research, many aspects of the HBV life cycle remain poorly characterized. In this review, we focus on the current understanding of the HBV life cycle and involved host factors, as well as potential targets for therapeutic intervention against HBV. We also consider possible immunotherapeutic strategies for eliminating HBV, including the removal of cccDNA from infected hepatocytes.
CD133 is a cellular surface protein, which has been reported to be a cancer stem cell marker, and thus is considered a potential target for cancer treatment. Metformin, one of the biguanides used for ...the treatment of diabetes, is also known to reduce the risk of cancer development and cancer stem-like cells (CSCs), including the expression of CD133. However, the mechanism underlying the reduction of the expression of CD133 by metformin is not yet understood. This study shows that metformin suppressed CD133 expression mainly by affecting the CD133 P1 promoter via adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling but not the mammalian target of rapamycin (mTOR). AMPK inhibition rescued the reduction of CD133 by metformin. Further experiments demonstrated that CCAAT/enhancer-binding protein beta (CEBPβ) was upregulated by metformin and that two isoforms of CEBPβ reciprocally regulated the expression of CD133. Specifically, the liver-enriched activator protein (LAP) isoform increased the expression of CD133 by directly binding to the P1 promoter region, whereas the liver-enriched inhibitory protein (LIP) isoform suppressed the expression of CD133. Consistent with these findings, a three dimensional (3D) culture assay and drug sensitivity assay demonstrated that LAP-overexpressing cells formed large spheroids and were more resistant to 5-fluorouracil (5-FU) treatment, whereas LIP-overexpressing cells were more sensitive to 5-FU and showed combined effects with metformin. Our results indicated that metformin-AMPK-CEBPβ signaling plays a crucial role in regulating the gene expression of CD133. Additionally, regulating the ratio of LAP/LIP may be a novel strategy for targeting CSCs for the treatment of cancer.
We previously revealed that Angiopoietin-2 (Ang2) predicts non-regression of liver fibrosis based on liver stiffness measurement (LSM) at 24 weeks after anti-hepatitis C virus (HCV) treatment. In ...this study, we extended the observational period to 96 weeks to investigate the factors associated with non-regression after treatment with direct-acting-antivirals (DAAs). Patients treated with DAAs who underwent transient elastography at baseline and 24 and 96 weeks after DAA therapy were included. Baseline and post-treatment serum Ang2 levels were measured. Liver fibrosis stages were defined based on LSM. Multivariate regression was used to evaluate factors associated with non-regression of liver fibrosis between various time points. In total, 110 patients were included. Of these, 11% showed non-regression of LSM-based fibrosis stage at 96 weeks after DAA therapy. In multivariate analysis, advanced liver fibrosis stage and high baseline Ang2 levels were significantly associated with non-regression at 96 weeks. In patients with advanced liver fibrosis (F3/4), baseline Ang2 levels were associated with non-regression of liver fibrosis stage. Between SVR24 and SVR96, post-treatment Ang2 levels and controlled attenuation parameter values at SVR24 were significantly associated with non-regression of liver fibrosis stage in patients with F3/4. Thus, serum Ang2 levels are an important target for monitoring and therapy.
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