Previous studies from western countries have reported that active hepatocellular carcinoma (HCC) was associated with direct-acting antiviral (DAA) treatment failure. We sought to examine this issue ...in an Asian cohort.
A retrospective cohort study was conducted on hepatitis C virus (HCV)-infected patients with advanced fibrosis who were treated with DAAs at our hospital between January 2017 and June 2018.
We treated 1021 HCV-infected patients during this period. A total of 976 of those patients were enrolled in a per-protocol analysis, including 556 (57.2%) who had genotype 1b infections, and 314 (32.3%) who had genotype 2 infections. The mean age of all 976 patients was 65.5 years, and 44.5% were male. 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. Non-sustained virologic response (SVR) was noted in 10 (1.3%) patients without HCC, 5 (2.9%) patients with inactive HCC, and 4 (13.0%) patients with active HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio AOR = 24.5 (95% confidence interval CI = 4.4-136.9), P<0.001). Next, we excluded the 23 patients with active HCC from the multivariate analysis. After adjustment for confounders, inactive HCC (versus non-HCC) was not associated with non-SVR (AOR = 3.1 (95% CI = 0.94-9.95), P = 0.06).
Active HCC was associated with non-SVR, while inactive HCC was not. We thus suggest the deferral of DAA treatment until after the complete radiological response of HCCs to treatment.
Reported herein is a Zn/Prophenol‐catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio‐ and diastereoselective construction of β‐fluoroamine ...motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted CF centers.
Work of a Pro: A Zn/Prophenol‐catalyzed direct Mannich reaction using α‐fluoroketones allows efficient construction of β‐fluoroamine motifs with high enantio‐ and diastereoselectivities. A stereocomplementary aldol reaction is also described. Boc=tert‐butoxycarbonyl.
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer, with dismal outcomes and an increasing incidence worldwide. Hepatocarcinogenesis is a multistep process that progresses ...from chronic hepatitis through cirrhosis and/or dysplastic nodule to HCC. However, the detailed molecular pathogenesis remains unclear. MicroRNAs (miRNAs), small noncoding RNAs that regulate the translation of many genes, have emerged as key factors involved in several biological processes, including development, differentiation, and cell proliferation. Recent studies have uncovered the contribution of miRNAs to the cancer pathogenesis, as they can behave as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential values in the clinical management of HCC patients as some miRNAs may be used as prognostic or diagnostic markers. In this review, we summarize current knowledge about the roles of miRNAs in carcinogenesis and progression of HCC. We also discuss the potential application of miRNAs as diagnostic biomarkers and their potential roles in the intervention of HCC.
Background and Aim
Noninvasive fibrosis indices can predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Modified FIB‐4 (mFIB‐4) is a promising noninvasive ...index for predicting liver fibrosis. To investigate the predictive accuracy of several extant noninvasive fibrosis indices, including mFIB‐4, for HCC incidence in CHB patients receiving long‐term entecavir therapy.
Methods
We enrolled 1325 nucleos(t)ide analogue‐naïve CHB patients (noncirrhotic 844; cirrhotic 481) treated with entecavir. Baseline clinical features and fibrosis indices were collected and evaluated for predicting HCC risk through univariate and multivariate Cox regression analyses.
Results
Of the 1325 patients, 105 (7.9%) developed HCC during a median follow‐up period of 4.1 years. Age (hazard ratio HR, 1.039; 95% confidence interval CI, 1.020–1.059; P < 0.0001), diabetes mellitus (DM) (HR, 1.902; 95% CI, 1.185–3.052; P = 0.0077), and mFIB‐4 (HR, 4.619; 95% CI, 1.810–11.789; P = 0.0014) were independent predictors of HCC in all patients (mFIB‐4 ≥ 1.5 for the noncirrhotic cohort; DM and mFIB‐4 ≥ 2.0 for the cirrhotic cohort). A combination of mFIB‐4 and the DM status stratified the cumulative risk of HCC into three subgroups in all patients (high: mFIB‐4 ≥ 1.5/DM; intermediate: mFIB‐4 ≥ 1.5/non‐DM; and low: mFIB‐4 < 1.5, P < 0.0001) and in the cirrhotic cohort (high: mFIB‐4 ≥ 2.0/DM; intermediate: mFIB‐4 ≥ 2.0/non‐DM; and low: mFIB‐4 < 2.0, P = 0.0007). An mFIB‐4 cutoff value of 1.5 stratified the cumulative risk of HCC in the noncirrhotic cohort (P = 0.015).
Conclusions
The mFIB‐4 index alone or in combination with DM is the optimal noninvasive predictor of HCC risk in CHB patients receiving entecavir therapy.
Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how ...polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin.
In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response SVR). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC.
The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC.
Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.
Background & Aims
Patients with chronic hepatitis C (CHC) after successful antiviral therapy remain at risk of hepatocellular carcinoma (HCC). This study was to determine whether liver stiffness ...measurement (LSM) was useful in HCC risk assessment and to develop a risk‐score system for clinical use.
Methods
This retrospective study enrolled patients with CHC achieving sustained virological response (SVR) after interferon‐based therapy with LSM at/after SVR determination. The demographics, clinical characteristics and HCC development were obtained from medical chart reviews. The diagnosis of HCC was based on recommended criteria.
Results
A total of 376 (M/F: 185/191, mean age: 54.1 years) patients, including 278 with pretreatment liver biopsy specimens, with a median follow‐up period of 7.6 years were enrolled. Twenty‐one patients developed HCC. The 5‐ and 10‐year cumulative HCC incidences were 1.4% and 7.8%, respectively. Multivariate analysis showed advanced fibrosis/cirrhosis, diabetes and LSM were associated with HCC developments with odds ratio (OR) of 12.38, 2.80 and 1.01, respectively. For LSM in HCC prediction, the performance and cut‐off were 0.783 and 12 kilopascal (kPa), respectively. For 278 patients with pretreatment biopsy, a risk‐score system (score 0–4) combining advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa was developed. With the low‐risk group as a reference, patients in intermediate‐ (OR: 12.57) and high‐risk (OR: 197.33) groups carried higher risk of HCC development.
Conclusions
For patients with CHC achieving SVR, liver stiffness value at/after SVR determination was associated with HCC development independently. Patients with pretreatment advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa after SVR were at high risk of HCC development.
This study investigated the kinetics in HBsAg and the HBsAg loss rate after entecavir or tenofovir disoproxil fumarate (TDF) cessation in patients with chronic hepatitis B (CHB) who achieved ...virological suppression after virological relapse without clinical relapse. A total 504 HBeAg-negative, non-cirrhotic patients who previously received entecavir or TDF with post-treatment and who were followed up for at least 30 months were included. Of the 504 patients, 128 achieved sustained virological suppression (Group I), and 81 experienced virological relapse without clinical relapse. Of the 81 patients, 52 had intermittent or persistent HBV DNA > 2000 IU/mL (Group II), and 29 achieved persistent virological suppression (HBV DNA < 2000 IU/mL) for at least 1.5 years (Group III) after virological relapse. A generalized estimating equations analysis showed that Groups I and III experienced larger off-treatment HBsAg declines than Group II (both, p < 0.001). The post-treatment HBsAg declines of Group I and Group III were similar (p = 0.414). A multivariate analysis showed that there were no differences in the HBsAg change and HBsAg decline (p = 0.920 and 0.886, respectively) or HBsAg loss rate (p = 0.192) between Group I and Group III. The patients who achieved persistent viral suppression after HBV relapse without clinical relapse have a similar decline in HBsAg and the HBsAg loss rate as the sustained responders.
There is strong evidence linking chronic hepatitis C virus (HCV) infection and Type 2 diabetes mellitus (DM). Recent studies have suggested that DM is associated with increased risk of developing ...hepatocellular carcinoma (HCC). The aim of our cohort study was to assess whether DM influence the incidence of HCC in chronic hepatitis C patients treated with interferon (IFN)‐based antiviral therapy. A total of 1,470 chronic hepatitis C patients treated with IFN or pegylated‐IFN plus ribavirin therapy were enrolled. Of them, 253 (17%) patients had DM at entry. Evaluation of HCC incidence was performed by Kaplan–Meier method and Cox proportional hazards analysis. Patients with baseline DM were significantly older and had higher body mass index, serum transaminase levels and fibrosis scores and lower platelet counts compared to non‐DM subjects. Sustained virological response (SVR) was achieved in 160 (63%) of DM and 867 (71%) of non‐DM patients (p = 0.008). During a median follow‐up period of 4.3 years, HCC developed in 21 (8.3%) of DM and 66 (5.4%) of non‐DM patients (p = 0.017). However, DM was not an independent covariate by Cox proportional hazards analysis. In a subgroup analysis, DM (hazard ratio, 4.32; 95% confidence interval, 1.23–15.25; p = 0.023) was an independent predictor of HCC in the SVR patients without baseline cirrhosis, despite a low HCC incidence. In conclusion, DM has a selective impact on HCC development among chronic hepatitis C patients after IFN‐based therapy. DM may increase the HCC risk in chronic hepatitis C without cirrhosis after eradication of HCV.
A recent meta-analysis revealed that the genotype PNPLA3 rs738409 GG is associated with a higher risk of hepatic steatosis (HS) in Caucasian patients with chronic hepatitis C (CHC). However, ...controversial results were found regarding Asian populations. Furthermore, previous studies have shown a negative association between interferon lambda 3 (IFNL3) rs12979860 CC and HS in Caucasian CHC patients, but there have been no reports indicating any such association in Asian populations. In this study, then, we investigated the association of PNPLA3 and IFNL3 polymorphisms with HS in Asian CHC patients.
We enrolled consecutive CHC patients who underwent liver biopsy prior to antiviral therapy. We excluded those patients with decompensated liver disease, any co-existing chronic liver disease, or HIV or HBV co-infection.
1080 CHC patients were enrolled, and HS was found in 453 (41.9%) patients. The frequency distribution of the G allele was significantly associated with HS (P<0.001), and this conferred a higher risk to G allele homozygotes (OR: 2.06, 95% CI: 1.46-2.88, P <0.001) than to G allele carriers (OR: 1.98, 95% CI: 1.52-2.58, P<0.001). There was a borderline significant difference in the prevalence of HS in rs12979860 CC versus non-CC (40.8% versus 49.3%, P = 0.059). After adjustment for age, sex, body mass index, diabetes, and excessive alcohol intake, the rs738409 G allele homozygote carriers still carried a higher risk for HS (OR: 1.93, 95% CI: 1.35-2.77, P = 0.003).
The PNPLA3 rs738409 GG genotype is positively associated with HS, while the IFNL3 rs 12979860 CC genotype may be negatively associated with HS, in Asian CHC patients.
Background & Aims
This study investigates the long‐term incidences and predictors of developing hepatocellular carcinoma (HCC), cirrhotic events and mortality in cirrhotic patients receiving ...entecavir (ETV) therapy.
Methods
We enrolled 481 nucleos(t)ide analogue‐naïve chronic hepatitis B (CHB) patients who had compensated cirrhosis upon entry and had received ETV monotherapy for >12 months.
Results
The 8‐year cumulative incidences of developing HCC, cirrhotic events and liver‐related mortality were 26.5%, 8.62% and 10.03% respectively. Multivariate analysis revealed that diabetic mellitus (DM), higher fibrosis‐4 (FIB‐4) and alpha‐foetoprotein (AFP) levels at 12 months of treatment, and FIB‐4 increase from baseline to 12 months were independent factors of HCC. FIB‐4 and AFP levels at 12 months of treatment were also independent factors of cirrhotic events and mortality. FIB‐4 cut‐off values of 3, 3 and 5 as well as AFP cut‐offs of 5, 5, and 9 ng/mL at 12 months of treatment were optimal for predicting HCC, cirrhotic events and mortality during therapy respectively. The FIB‐4 and AFP levels at 12 months of treatment were assessed for the combined risk of developing clinical outcomes. The 8‐year incidences of HCC, cirrhotic events and liver‐related mortality in the subgroups with low FIB‐4 and AFP levels were only 5.95%, 1.03% and 2.43% respectively. DM was an independent predictor of HCC and mortality.
Conclusion
The combination of FIB‐4 and AFP levels at 12 months of treatment is a useful marker for predicting the development of HCC, cirrhotic events and mortality in compensated cirrhotic patients with CHB who are receiving ETV therapy.
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