The long‐term clinical impact of low‐level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change ...in therapy. A retrospective cohort of 875 treatment‐naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 65.5%, cirrhosis = 443 50.6%) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow‐up (range 1.0‐8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28‐3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34‐3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. Conclusion: LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335–343).
Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, ...randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC.
Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety.
The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio HR, 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively.
Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.
This study aimed to investigate the association of nonalcoholic fatty liver disease (NAFLD) and its severity with the decline in kidney function in patients with chronic kidney disease (CKD). We ...conducted a cohort study of 1,525 CKD patients who underwent repeated health check-up examinations from January 2003 through December 2013. NAFLD was diagnosed by ultrasonography and its severity was assessed by the NAFLD fibrosis score. At baseline, the prevalence of NAFLD was 40.9%, and the mean estimated glomerular filtration rate (eGFR) was 59.1 ml/min/1.73 m
. The average follow-up was 6.5 years. The age- and sex-adjusted decline in eGFR was greater in patients with NAFLD (-0.79% per year, 95% CI -1.31%, -0.27%) compared to those without it (0.30%, 95% CI -0.14%, 0.76%; p = 0.002). In multivariable adjusted models, the average difference in annual percent change in decline in eGFR comparing patients with NAFLD to those without NAFLD was -1.06% (-1.73%, -0.38%; p = 0.002). The decline in eGFR associated with NAFLD was greater in patients with higher NAFLD fibrosis score, in those with proteinuria or with low eGFR at baseline ( <45 ml/min/1.73 m
), and in those who were smokers and hypertensive. Therefore, NAFLD is independently associated with CKD progression.
Here, a new medium, named intensive soil extract medium (ISEM), based on new soil extract (NSE) using 80% methanol, was used to efficiently isolate previously uncultured bacteria and new taxonomic ...candidates, which accounted for 49% and 55% of the total isolates examined (
= 258), respectively. The new isolates were affiliated with seven phyla (
,
,
,
,
,
, and
). The result of chemical analysis showed that NSE included more diverse components of low-molecular-weight organic substances than two conventional soil extracts made using distilled water. Cultivation of previously uncultured bacteria is expected to extend knowledge through the discovery of new phenotypic, physiological, and functional properties and even roles of unknown genes.
Both metagenomics and single-cell sequencing can detect unknown genes from uncultured microbial strains in environments, and either method may find the significant potential metabolites and roles of these strains. However, such gene/genome-based techniques do not allow detailed investigations that are possible with cultures. To solve this problem, various approaches for cultivation of uncultured bacteria have been developed, but there are still difficulties in maintaining pure cultures by subculture.
Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon ...alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B.
A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks.
After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent P<0.001 and 27 percent vs. 19 percent P=0.02, respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent P=0.01 and 34 percent vs. 22 percent P=0.003, respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died.
In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.
Background and Aim
Non‐alcoholic fatty liver disease (NAFLD) is a multisystem disease associated with an increased risk of cardiovascular disease (CVD), diabetes, and chronic kidney disease. Indeed, ...CVD is the most common cause of death in NAFLD patients. This study aimed to evaluate the association between NAFLD and the risk of incident myocardial infarction.
Methods
This is a retrospective cohort study involving 111 492 adults over 40 years old without history of CVD, liver disease, or cancer at baseline who participated in a regular health screening exam between 2003 and 2013. Fatty liver was diagnosed by ultrasonography.
Results
During 725 706.9 person‐years of follow‐up, 183 participants developed myocardial infarction (incidence rate 0.3 cases per 1000 person‐years). The age, sex, and year of visit‐adjusted hazard ratio (HR) for incident myocardial infarction comparing participants with NAFLD with those without it was 2.14 (95% confidence interval 1.59, 2.89). This association remained significant in fully adjusted models (HR 1.54; 95% confidence interval 1.11, 2.14). Compared with participants without NAFLD, in participants with low NAFLD fibrosis score (NFS) (< −1.455) and with intermediate‐to‐high NFS (≥ −1.455), the fully adjusted HRs for incident myocardial infarction were 1.70 (1.22, 2.36) and 1.88 (1.24, 2.87), respectively.
Conclusion
In this large cohort study, NAFLD was associated with an increased incidence of myocardial infarction independently of established risk factors. In addition, this association was similar in participants with and without evidence of more advanced NAFLD as indicated by the NFS. NAFLD patients may need to be carefully monitored and managed early to prevent myocardial infarction.
The ursodeoxycholic acid (UDCA) response score (URS) was developed to identify poor responders to UDCA before treatment, in order to offer timely and proactive intervention. However, validation of ...the URS in Asian population is warranted.
A total of 173 Asian patients diagnosed with primary biliary cholangitis (PBC) between 2007 and 2016 at seven academic institutions in Korea who started UDCA treatment were analyzed to validate the performance of URS. UDCA response was defined as an alkaline phosphatase level less than 1.67 times the upper limit of normal after 1-year of UDCA treatment. In addition, prognostic performance of URS for liver-related events, defined as newly developed hepatic decompensation or hepatocellular carcinoma was evaluated.
After 1 year of UDCA treatment, 133 patients (76.9%) achieved UDCA response. UDCA response rate was 98.7% for those with URS ≥1.41 (n=76) and 58.8% for those with URS <1.41 (n=97). The area under the receiver operating characteristic curve of URS in predicting UDCA response was 0.84 (95% confidence interval, 0.78 to 0.88). During a median follow-up of 6.5 years, liver-related events developed in 18 patients (10.4%). Among 117 patients with PBC stage I-III by histological evaluation, the 5-year liver-related event-free survival rate differed according to the URS; 100% for URS ≥1.41 and 86.5% for URS <1.41 (p=0.005).
URS demonstrated good performance in predicting a UDCA treatment response in Asian PBC patients. In addition, the risk of liver-related events differed according to the URS for the PBC stage. Thus, URS can be used to predict the response and clinical outcome in patients with PBC.
Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, was associated with subclinical atherosclerosis in many cross-sectional studies, but the prospective ...association between NAFLD and the progression of atherosclerosis has not been evaluated. This study was conducted to evaluate the association between NAFLD and the progression of coronary atherosclerosis.
This retrospective cohort study included 4731 adult men and women with no history of cardiovascular disease (CVD), liver disease or cancer at baseline who participated in a repeated regular health screening examination between 2004 and 2013. Fatty liver was diagnosed by ultrasound based on standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls. Progression of coronary artery calcium (CAC) scores was measured using multidetector CT scanners.
The average duration of follow-up was 3.9 years. During follow-up, the annual rate of CAC progression in participants with and without NAFLD were 22% (95% CI 20% to 23%) and 17% (16% to 18%), respectively (p<0.001). The multivariable ratio of progression rates comparing participants with NAFLD with those without NAFLD was 1.04 (1.02 to 1.05; p<0.001). The association between NAFLD and CAC progression was similar in most subgroups analysed, including in participants with CAC 0 and in those with CAC >0 at baseline.
In this large cohort study of adult men and women with no history of CVD, NAFLD was significantly associated with the development of CAC independent of cardiovascular and metabolic risk factors. NAFLD may play a pathophysiological role in atherosclerosis development and may be useful to identify subjects with a higher risk of subclinical disease progression.
Background & Aims Nonalcoholic fatty liver disease (NAFLD) has been associated with subclinical atherosclerosis in cross-sectional studies. We investigated the longitudinal association of NAFLD with ...the development of subclinical carotid atherosclerosis. Methods We performed a retrospective cohort study of 8020 adult men (average age, 49.2 y) without carotid atherosclerosis at baseline who underwent repeated health check-up examinations from January 1, 2005, through December 31, 2013. NAFLD status was diagnosed by ultrasonography and classified into 4 groups based on baseline and follow-up findings: none, developed, regressed, or persistent NAFLD. Subclinical carotid atherosclerosis was measured by ultrasound. Results The age-adjusted hazard ratio for subclinical carotid atherosclerosis development comparing participants with persistent NAFLD with those without NAFLD was 1.23 (95% confidence interval CI, 1.13–1.35; P < .001). The association persisted after adjustment for smoking, alcohol, body mass index, and weight change (hazard ratio, 1.13; 95% CI, 1.03–1.25; P = .014), but disappeared after adjustment for metabolic variables. The hazard ratio, comparing subjects with regression of NAFLD vs those with persistent NAFLD, was 0.82 (95% CI, 0.69–0.96; P = .013). The risk of subclinical carotid atherosclerosis development also was higher among participants with a high NAFLD fibrosis score, fibrosis-4 scores, or levels of γ-glutamyl transferase at baseline. Conclusions In a large cohort study, persistent NAFLD was associated with an increased risk of subclinical carotid atherosclerosis development. This association was explained by metabolic factors that could be potential mediators of the effect of NAFLD. Markers of liver fibrosis also were associated with subclinical carotid atherosclerosis development. Prospective studies are needed to determine whether treatment of NAFLD can reduce this risk.
Given the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT ...improves patient outcome is limited.
We performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396).
In the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval CI; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR 95% CI = 0.67 0.56-0.80). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml).
MDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations.
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