Background
In Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir–velpatasvir with or ...without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis Child–Pugh–Turcotte (CPT) class B or C in Japan.
Methods
Patients were randomized 1:1 to receive sofosbuvir–velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint.
Results
Of the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41–83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir–velpatasvir and seven (14%) who received sofosbuvir–velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression.
Conclusion
Sofosbuvir–velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.
Ruxolitinib is a useful treatment option for myelofibrosis since it effectively resolves splenomegaly and constitutional symptoms. After the widespread use of ruxolitinib outside of clinical trials, ...a series of case reports indicated a potential risk of ruxolitinib-associated opportunistic infections, including the reactivation of the hepatitis B virus (HBV). We herein report the case of a polycythemia vera patient who showed an elevation of HBV-DNA viral DNA with an elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) after the initiation of ruxolitinib. Anti-viral therapy with entecavir was immediately started and the HBV viral load thereafter decreased with an improvement of the liver function. Physicians should thus be aware of the potential risk of ruxolitinib-associated HBV reactivation.
Background and Aims
Genetic alterations in specific genes are critical events in carcinogenesis and hepatocellular carcinoma (HCC) progression. However, the genetic alterations responsible for HCC ...development, progression, and survival are unclear.
Methods
We investigated the essential difference in genetic alterations between HCC and adjacent non-HCC tissues using next-generation sequencing technology.
Results
We found recurrent mutations in several genes such as telomerase reverse transcriptase (
TERT
; 65 % of the total 104 HCCs),
TP53
(38 %),
CTNNB1
(30 %),
AXIN1
(2 %),
PTEN
(2 %), and
CDKN2A
(2 %).
TERT
promoter mutations were associated with older age (
p
= 0.005), presence of hepatitis C virus (HCV) infection (
p
= 0.003), and absence of hepatitis B virus (HBV) infection (
p
< 0.0001). In hepatitis B surface antigen (HBs Ag)-positive HCC without
TERT
promoter mutations, HBV integration into
TERT
locus was found in 47 % patients and was mutually exclusive to
TERT
promoter mutations. Most (89 %) HBV integrants were in the HBx region.
TP53
mutations were associated with HBV infection (
p
= 0.0001) and absence of HCV infection (
p
= 0.002).
CTNNB1
mutations were associated with absence of HBV infection (
p
= 0.010). Moreover,
TERT
promoter mutation was significantly associated with shorter disease-free survival (
p
= 0.005) and poor overall survival (
p
= 0.024).
Conclusions
Gene alterations in
TERT
promoter,
TP53
,
CTNNB1
, and HBV integration were closely associated with HCC development, and mutations in
TERT
promoter are related to poor prognosis. These results are useful for understanding the underlying mechanism of hepatocarcinogenesis, diagnosis, and predicting outcomes of patients with HCC.
Abstract
Annual rings record the intensity of cosmic rays (CRs) that had entered into the Earth’s atmosphere. Several rapid
14
C increases in the past, such as the 775 CE and 994CE
14
C spikes, have ...been reported to originate from extreme solar proton events (SPEs). Another rapid
14
C increase, also known as the ca. 660 BCE event in German oak tree rings as well as increases of
10
Be and
36
Cl in ice cores, was presumed similar to the 775 CE event; however, as the
14
C increase of approximately 10‰ in 660 BCE had taken a rather longer rise time of 3–4 years as compared to that of the 775 CE event, the occurrence could not be simply associated to an extreme SPE. In this study, to elucidate the rapid increase in
14
C concentrations in tree rings around 660 BCE, we have precisely measured the
14
C concentrations of earlywoods and latewoods inside the annual rings of Japanese cedar for the period 669–633 BCE. Based on the feature of
14
C production rate calculated from the fine measured profile of the
14
C concentrations, we found that the
14
C rapid increase occurred within 665–663.5 BCE, and that duration of
14
C production describing the event is distributed from one month to 41 months. The possibility of occurrence of consecutive SPEs over up to three years is offered.
Background & Aims Pegylated interferon and ribavirin (PEG-IFN/RBV) therapy for chronic hepatitis C virus (HCV) genotype 1 infection is effective in 50% of patients. Recent studies revealed an ...association between the IL28B genotype and treatment response. We aimed to develop a model for the pre-treatment prediction of response using host and viral factors. Methods Data were collected from 496 patients with HCV genotype 1 treated with PEG-IFN/RBV at five hospitals and universities in Japan. IL28B genotype and mutations in the core and IFN sensitivity determining region (ISDR) of HCV were analyzed to predict response to therapy. The decision model was generated by data mining analysis. Results The IL28B polymorphism correlated with early virological response and predicted null virological response (NVR) (odds ratio = 20.83, p <0.0001) and sustained virological response (SVR) (odds ratio = 7.41, p <0.0001) independent of other covariates. Mutations in the ISDR predicted relapse and SVR independent of IL28B . The decision model revealed that patients with the minor IL28B allele and low platelet counts had the highest NVR (84%) and lowest SVR (7%), whereas those with the major IL28B allele and mutations in the ISDR or high platelet counts had the lowest NVR (0–17%) and highest SVR (61–90%). The model had high reproducibility and predicted SVR with 78% specificity and 70% sensitivity. Conclusions The IL28B polymorphism and mutations in the ISDR of HCV were significant pre-treatment predictors of response to PEG-IFN/RBV. The decision model, including these host and viral factors may support selection of optimum treatment strategy for individual patients.
Aim
Although the viral markers hepatitis B surface antigen (HBsAg) and hepatitis B core‐related antigen (HbcrAg) could reflect intrahepatic hepatitis B virus (HBV) replication activity and constitute ...important biomarkers for hepatocellular carcinoma (HCC), the value of using these two markers in combination for assessing HCC risk has not been clarified in detail.
Methods
Four hundred and forty‐nine consecutive patients with chronic HBV infection were included in the study and the association of HBsAg and HBcrAg with HCC risk was investigated cross‐sectionally, as well as longitudinally.
Results
When the high value cut‐offs of HBsAg and HBcrAg were defined as 3.0 log IU/mL and 3.0 log U/mL, respectively, patients with a history of HCC were found frequently in the low HBsAg group (P = 0.002) and high HBcrAg group (P < 0.001). When HBsAg and HBcrAg were combined, an HCC history was most frequent in the subset with low HBsAg and high HBcrAg, among the HBeAg‐negative patients (odds ratio OR, 7.83; P < 0.001), irrespective of nucleos(t) ide analogue (NA) therapy (NA: OR, 4.76; P < 0.001; non‐NA: OR, 9.60; P < 0.001). In a longitudinal analysis of the subsequent development of HCC, carried out on the 338 patients without an HCC history at enrollment, HCC developed significantly more frequently in the low HBsAg/high HBcrAg group (P = 0.005).
Conclusions
Patients with low HBsAg/high HBcrAg values are at high risk of developing HBV‐related HCC, according to this cross‐sectional and longitudinal analysis, indicating that the combination of HBsAg and HBcrAg values is an excellent biomarker for assessing HCC risk.
Background
This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C.
Methods
Data ...from 800 genotype 1b chronic hepatitis C patients with high viral load (>100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (
n
= 506) or an internal validation (
n
= 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis.
Results
Age (<50 years), alpha-fetoprotein (AFP) (<8 ng/mL), platelet count (≥120 × 10
9
/l), gamma-glutamyltransferase (GGT) (<40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (
r
2
= 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group.
Conclusions
A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy.
In radiocarbon dating, it is necessary to correct the measured radiocarbon ages to calendar ages based on a calibration curve. The IntCal calibration curve applied to terrestrial materials in the ...Northern Hemisphere has been developed mainly on the basis of tree ring materials from Europe and the United States, but research in Japan has also played a major role, such as the varved sediment of Lake Suigetsu, Fukui Prefecture, and the Japanese tree rings used in IntCal20. The history of the latest calibration curve IntCal20 is outlined, focusing on the efforts made in Japan.
Aim
Liver fibrosis is a risk factor for hepatocellular carcinoma (HCC), but at what fibrotic stage the risk for HCC is increased has been poorly investigated quantitatively. This study aimed to ...determine the appropriate cut‐off value of liver stiffness for HCC concurrence by FibroScan, and its clinical significance in hepatitis B virus (HBV), hepatitis C virus (HCV) and non‐B, non‐C (NBNC) liver disease.
Methods
Subjects comprised 1002 cases (246 with HCC and 756 without HCC) with chronic liver disease (HBV, 104; HCV, 722; and NBNC, 176).
Results
Liver stiffness was significantly greater in all groups with HCC, and the determined cut‐off value for HCC concurrence was more than 12.0 kPa in those with HCV, more than 8.5 kPa in those with HBV and more than 12.0 kPa in those with NBNC. Liver stiffness of more than 12.0 kPa was an independent risk factor for new HCC development in HCV. For HCV, risk factors for HCC concurrence were old age, male sex, low albumin, low platelets and liver stiffness, while for HBV they were old age, low platelets and liver stiffness, and for NBNC they were old age, elevated α‐fetoprotein and liver stiffness.
Conclusion
Liver stiffness cut‐off values and their association with HCC concurrence were different depending on the etiology. In HCV, liver stiffness of more than 12.0 kPa was an independent risk factor for new HCC development. Collectively, determining the fibrotic cut‐off values for HCC concurrence would be important in evaluating HCC risks.
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