Background
Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the ...NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment.
Methods
In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed.
Results
Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (
p
= 0.008) with HCV genotype except 3 (genotype 1 vs. 3,
p
= 2.68 × 10
–5
; genotype 2 vs. 3,
p
= 3.28 × 10
–5
) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% 1209/1220) and chronic kidney disease (CKD) stage 4–5 (98.9% 188/190) patients, or between cirrhotic (99.0% 398/402) and non-cirrhotic (99.1% 999/1008) patients. Multiple logistic regression analysis revealed that genotype 3 OR 33.404, 95% CI (7.512–148.550),
p
value (
p
= 4.06 × 10
–5
) and past experience of IFN-free DAAs OR 3.977, 95% CI (1.153–13.725),
p
value (
p
= 0.029) were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% 79/190) than CKD stage 1–3 (26.1% 319/1220) patients (
p
= 2.00 × 10
–5
). AEs were also significantly higher in cirrhotic (38.6% 155/402) than in non-cirrhotic (24.1% 243/1008) (
p
= 2.91 × 10
–18
) patients.
Conclusions
G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.
Aim
Predicting the survival of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/bev) remains a challenge. This study aims to validate the modified ...albumin–bilirubin grade and α-fetoprotein score (mALF score).
Methods
This retrospective, multicenter study included 426 HCC patients receiving Atez/Bev. Each patient was randomized 3:2 to a training set (
n
= 255) and a validation set (
n
= 171). We investigated prognostic factors in the training set and developed an easily applicable mALF score, which was evaluated in the validation set.
Results
We built the mALF score using baseline mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37–4.05,
p
= 0.002) and α-fetoprotein ≥ 100 ng/ml (HR 2.61, 95% CI 1.49–4.55,
p
< 0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9–90.8) in patients who meet neither of the criteria (mALF 0 points,
n
= 101), 61.7% (95% CI 44.5–74.9) in patients who meet either of the two criteria (mALF 1 point,
n
= 109), and 24.6% (95% CI 9.0–44.3) in patients who meet both criteria (mALF 2 points, n = 45); the difference was statistically significant (
p
< 0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0–8.0), and 3.8 months (95% CI 3.0–5.2), respectively, which amounted to a significant difference (
p
< 0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points = 94.2%/62.1%/46.3%,
p
< 0.001; median PFS, 0/1/2 points = 9.3/6.7/4.7 months,
p
= 0.018).
Conclusion
The mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.
Aim
There have been no established predictors of the outcome on sorafenib therapy for hepatocellular carcinoma (HCC) patients. We aimed to establish a new prognostic model suitable for sorafenib in ...HCC.
Methods
Among 465 HCC patients treated with sorafenib in 14 hospitals, we formed a training cohort with 270 patients at seven hospitals located in West Japan and a validation cohort with 167 patients at seven hospitals located in East Japan. In the training cohort, we examined the relationship between overall survival (OS) and pretreatment clinical factors, and structured a new prognostic model. We verified this model in the validation cohort and compared with four existing staging models.
Results
Multivariate analysis demonstrated distant metastases, portal invasion, intrahepatic tumor burden of more than 50%, serum α‐fetoprotein of 150 ng/dL or more, des‐γ‐carboxyprothrombin of 1200 mAU/mL or more, albumin of 3.5 g/dL or less and total bilirubin of more than 1.0 mg/dL were significant independent adverse prognostic factors. We calculated a Japan Red Cross (JRC) score with these factors and classified three groups: low‐, intermediate‐ or high‐risk. Their median OS were well stratified (18.0, 8.8 and 3.7 months, respectively, P < 0.001) in the training cohort. In the validation cohort, OS were also statistically stratified (23.9, 10.3 and 2.9 months, P < 0.001). C‐statistics of the JRC score was 0.755, the highest in the five models, indicating its novel predictability.
Conclusion
Our proposed JRC score well predicts the prognosis of sorafenib therapy, and would be useful to plan individualized strategies for unresectable HCC.
Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)–infected patients who are ...direct‐acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real‐world experience with 8‐week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8‐week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention‐to‐treat population and 99.3% (526/530) in the per‐protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8‐week treatment with G/P, none had baseline polymorphisms or treatment‐emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment‐emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug‐related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA‐naïve noncirrhotic genotype 1 or 2 patients in a real‐world clinical setting in Japan.
Background
The virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with ...hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings.
Methods
In a Japanese nationwide multicenter study, the rate of sustained virologic response (SVR) and safety were analyzed in 91 patients who started the DCV/ASV/BCV regimen between November 2016 and July 2017. SVR rates were compared based on baseline patient characteristics.
Results
More than 60% of patients had a history of failure to achieve SVR with interferon (IFN)-free DAA therapy. Overall, 50 of 91 patients (54.9%) achieved SVR. Multivariate analysis identified a history of failure with IFN-free DAA therapy and pretreatment HCV RNA levels as factors significantly associated with treatment failure. Whereas the SVR rate in patients without a history of IFN-free DAA therapy was 91.7% (33 of 36 patients), it was only 30.9% (17 of 55 patients) among patients with a history of IFN-free DAA therapy. The rate of discontinuation due to an adverse event was 4.4%.
Conclusions
Many patients treated with the DCV/ASV/BCV regimen have a history of a failure to achieve SVR with previous IFN-free DAA therapy. SVR rate was not as high as that in pre-approval clinical trial of this regimen in IFN-free DAA-naïve patients. In addition, most patients with a history of failure with IFN-free DAA therapy, particularly the DCV/ASV regimen, showed resistance to this regimen.
Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present ...phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14–21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0–2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0–1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval CI 25.1–31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months–NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.
Computed tomography (CT) is often used in the diagnosis of sarcopenia. In this study, we validated the assessment of sarcopenia by the psoas muscle volume using versatile software. The study involved ...a retrospective analysis of data from 190 patients with liver disease who underwent grip-strength testing and abdominal pelvic computed tomography. To assess sarcopenia, SYNAPSE 3D was used to obtain the skeletal muscle index, the psoas muscle index (PMI), and the simple method. We also used the recently proposed PMI cutoff values, for which the usefulness has been evaluated (O-PMI). The cutoff value of the psoas muscle volume index (PMVI) was determined using one of the diagnostic methods as the gold standard. All diagnostic methods showed that patients with sarcopenia had shorter survival, with O-PMI having the highest hazard ratio (HR) (HR, 6.12; 95% confidence interval CI, 2.6-14.41;
< 0.001). Even when sarcopenia could not be diagnosed by O-PMI, low PMVI was associated with shorter survival (HR, 3.53; 95% CI, 1.34-9.32;
= 0.01). PMVI may be useful in the evaluation of sarcopenia, including the identification of poor overall survival in cases that cannot be diagnosed by O-PMI, which is considered more useful than PMI.
Aim
Recently, the neo‐Glasgow prognostic score (GPS), a composite biomarker determined by the C‐reactive protein level and albumin–bilirubin grade, was developed to predict outcomes in hepatocellular ...carcinoma (HCC) patients who undergo hepatic resection. The present research investigated whether the neo‐GPS could predict prognosis in HCC patients treated with atezolizumab plus bevacizumab (Atez/Bev).
Methods
A total of 421 patients with HCC who were treated with Atez/Bev were investigated.
Results
Multivariate Cox hazards analysis showed that a GPS of 1 (hazard ratio (HR), 1.711; 95% confidence interval (CI), 1.106–2.646) and a GPS of 2 (HR, 4.643; 95% CI, 2.778–7.762) were independently associated with overall survival. Conversely, multivariate Cox hazards analysis showed that a neo‐GPS of 1 (HR, 3.038; 95% CI, 1.715–5.383) and a neo‐GPS of 2 (HR, 5.312; 95% CI, 2.853–9.890) were also independently associated with overall survival in this cohort. Additionally, cumulative overall survival rates differed significantly by GPS and neo‐GPS (p < 0.001). The neo‐GPS, compared with the GPS, had a lower Akaike information criterion (1207 vs. 1,211, respectively) and a higher c‐index (0.677 vs. 0.652, respectively) regarding to overall survival. In a subgroup analysis of patients considered to have a good prognosis as confirmed using a Child–Pugh score of 5 (p = 0.001), a neutrophil‐to‐lymphocyte ratio <3 (p = 0.001), or an α‐fetoprotein level < 100 ng/mL (p < 0.001), those with a high neo‐GPS (≥1) had a statistically poorer overall survival than those with a low neo‐GPS.
Conclusions
The neo‐GPS can predict prognosis in advanced unresectable HCC patients treated with Atez/Bev.
The neo‐Glasgow prognostic score, based on C‐reactive protein level and albumin‐bilirubin grade, was developed as a new biomarker for hepatocellular carcinoma. High neo‐Glasgow prognostic scores were associated with poor outcomes in patients treated with atezolizumab plus bevacizumab.In comparison with the Glasgow prognostic score, the neo‐Glasgow prognostic score was associated with a lower Akaike information criterion value and higher c‐index for overall survival.
Introduction: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered a safe and minimally invasive procedure. We previously reported that the mortality and complication rates ...for RFA were 0.038% (5/13,283 patients) and 3.54% (579 complications/16,346 procedures), respectively, from 1999 to 2010 (previous period). In this study, we investigated the clinical criteria for RFA and the mortality and complication rates from 2011 to 2015 (recent period). Methods: Data were collected from 25 centers by using a questionnaire developed by the Chugoku-Shikoku Society for Local Ablation Therapy of HCC. The criteria for RFA, RFA modification, use of image-guidance modalities, mortality, and complications during the previous and recent periods were compared. Results: We evaluated 11,298 procedures for 9,411 patients, including those that involved new devices (bipolar RFA and internally adjustable electrode system). The criterion of hepatic function for RFA increased from a Child-Pugh score ≤8 during the previous period to ≤9 during the recent period. The criteria regarding the tumor location and other risk factors have been expanded recently because of the increased use of several modifications of the RFA procedure and image-guidance modalities. The mortality rate was 0.064% (6/9,411 patients), and the complication rate was 2.92% (330 complications/11,298 procedures). There was no difference in mortality rates between the 2 periods (p = 0.38), but the complication rates was significantly lower during the recent period (p = 0.038). Discussion and Conclusions: Our findings confirmed that RFA, including the use of new devices, is a low-risk procedure for HCC, despite the expansion of the criteria for RFA during the recent period.
Introduction Abdominal angiography procedures such as transarterial chemoembolization (TACE) are essential for hepatocellular carcinoma treatment. One method commonly used is transfemoral access ...(TFA). However, issues associated with this method, which include postoperative compression of the puncture site and long periods of bed rest, can affect patient satisfaction. Thus, transradial access (TRA), a minimally invasive treatment method that improves treatment quality, was developed for TACE. This retrospective, multicenter study aimed to investigate the efficacy and safety of abdominal angiography using the radial artery approach. Methods In total, 1,601 patients underwent abdominal angiography using TRA and received treatment (radial access for visceral intervention (RAVI)) at 14 institutions in Japan. The treatment time, procedure completion rate, patient satisfaction, and complications were investigated. Results The success rate of RAVI was 99.4%, and the complication rate was 1.2%. Approximately 98.2% of the patients requested the radial artery approach again. There were no significant differences in the success rate of RAVI and the incidence of complications based on the operator's years of experience or the patient's age. Some patients developed minor complications such as puncture site bleeding, hematoma, vascular pain, and vasospasm. Further, serious complications (cerebral infarction (n = 1), cerebellar infarction (n = 1), and aortic dissection (n = 1)) were observed. Conclusion Similar to the conventional TFA, RAVI helped in facilitating peritoneal angiography safely. In abdominal angiography, this method can reduce patient burden and can be widely used in the future from the perspective of clinical benefit.
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