Post-treatment levels of α-fetoprotein predict long-term hepatocellular carcinoma development after sustained virological response in patients with hepatitis C.

AIM: The rate of hepatocellular carcinoma (HCC) development is reportedly lower in patients with chronic hepatitis C virus (HCV) who have achieved a sustained virological response (SVR) than in patients who were unresponsive to therapy. However, the development of HCC is sometimes observed in patients with SVR. Therefore, we clarified the predictive power of clinical factors for HCC incidence in patients with SVR using receiver operating characteristic (ROC) curve analysis that takes time dependence into account. METHODS: A total of 571 patients with HCV who achieved SVR with interferon-based therapy were enrolled. Univariate and multivariate Cox proportional hazards models and time-dependent ROC curves were used to analyze clinical factors associated with the development of HCC. RESULTS: Twenty-four patients developed HCC during the follow-up period (median duration, 9.0 years). The 5-, 10-, 15-, and 20-year cumulative incidence rates for HCC were 1.7%, 4.8%, 5.8%, and 6.6%, respectively. Multivariate Cox proportional hazards models showed that older age (hazard ratio [HR], 3.648), male sex (HR, 7.560), lower platelet count at 24 weeks after the end of treatment (SVR24) (HR, 3.939), and higher α-fetoprotein (AFP) at SVR24 (HR, 3.630) were independently associated with HCC development. In addition, time-dependent ROC analysis showed that, compared to platelet count at SVR24, AFP at SVR24 had higher predictive power for HCC incidence approximately 7 years after SVR. CONCLUSIONS: Elevated AFP at SVR24 is a risk factor for HCC in patients with HCV, even those who achieve SVR. α-Fetoprotein is a good predictor of HCC development.

Viral eradication reduces all-cause mortality, including non-liver-related disease, in patients with progressive hepatitis C virus-related fibrosis.

BACKGROUND AND AIM: Eradication of hepatitis C virus (HCV) with interferon (IFN)-based therapy has been reported to reduce all-cause mortality in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality and causes of death has not been sufficiently investigated in patients with progressive HCV-related fibrosis. METHODS: We enrolled 784 chronic HCV patients with progressive liver fibrosis (aspartate aminotransferase to platelet ratio index >1). Cause of death, incidence of hepatocellular carcinoma, and all-cause mortality including non-liver-related mortality were analyzed. RESULTS: Of these 784 patients, 170 achieved sustained virological response (SVR) (eradication of HCV) with IFN-based therapy (IFN-SVR), and 614 did not receive IFN-based therapy (non-IFN patients, chronic HCV infection). The median follow-up duration was 10.3 years. Two hundred seventy-three patients died during follow-up (liver-related death, n = 171; non-liver-related death, n = 102). The mortality rate from non-liver-related disease was 63.6% (7/11) in IFN-SVR patients and 36.3% (95/262) in non-IFN patients, respectively. In multivariate analysis, the eradication of HCV associated with not only hepatocellular carcinoma incidence (hazard ratio (HR), 0.162; 95% confidence interval (CI), 0.092-0.284), and all-cause mortality (HR, 0.094; 95% CI, 0.047-0.187), but non-liver-related mortality (HR, 0.286; 95% CI, 0.127-0.644) as well. CONCLUSIONS: Eradication of HCV reduced both liver-related and non-liver-related mortality in patients with progressive HCV-related fibrosis.

HBcrAg predicts hepatocellular carcinoma development: An analysis using time-dependent receiver operating characteristics.

BACKGROUND & AIMS: Several hepatitis B virus (HBV) markers have been identified as factors associated with the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We clarified the predictive power of HBV markers for the development of HCC using receiver operating characteristic (ROC) analysis with a consideration of time dependence. METHODS: A total of 1031 CHB patients who were not treated with nucleos(t)ide analogue therapy were enrolled. Univariate, multivariate, and time-dependent ROC curves for HBV markers associated with the development of HCC were analyzed. RESULTS: Seventy-eight patients developed HCC during the follow-up period (median duration 10.7years). Different levels or statuses of several HBV markers (HBV genotype, HBV DNA, HBV core-related antigen (HBcrAg), hepatitis B e antigen (HBeAg), and basal core promoter (BCP)), but not hepatitis B surface antigen, were significantly associated with the incidence of HCC by univariate analysis using the log-rank test. Cox proportional hazards models using the covariates of HBV genotype status, HBV DNA levels, HBcrAg levels, HBeAg status, and BCP status indicated that HBcrAg >2.9logU/ml (hazard ratio (HR), 5.05; 95% confidence interval (CI), 2.40-10.63) and BCP mutation (HR, 28.85; 95% CI, 4.00-208.20) were independently associated with the incidence of HCC. Additionally, time-dependent ROC analysis showed that HBcrAg was superior to HBV DNA in terms of predictive power for HCC development throughout the follow-up period. CONCLUSIONS: Elevation of HBcrAg levels in CHB patients is associated with the development of HCC. HBcrAg is an excellent predictor of HCC development. LAY SUMMARY: Hepatitis B virus (HBV) core-related antigen (HBcrAg) is an excellent predictor of hepatocellular carcinoma (HCC) development in chronic hepatitis B patients without nucleos(t)ide analogue therapy. HBcrAg was superior to HBV DNA in terms of predictive power for HCC development by time-dependent receiver operating characteristic analysis.

Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis.

BACKGROUND & AIMS: Eradication of hepatitis C virus (HCV) by interferon (IFN)-based therapy has been reported to reduce all-cause mortality rates in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality including the causes of death has not been sufficiently investigated in patients with chronic HCV infection. METHODS: We enrolled 2743 patients with chronic HCV infection. Causes of death, incidence of hepatocellular carcinoma (HCC), and all-cause mortality including non-liver-related diseases, were analysed. RESULTS: Of these 2743 patients, 587 achieved sustained virological response (SVR) (eradication of HCV) by IFN-based therapy (IFN-SVR), 475 did not (without HCV eradication) (IFN-non-SVR), or 1681 did not receive IFN-based therapy (non-IFN patients) (Cohort 1); of these, 309 were selected from IFN-SVR and non-IFN groups using propensity score matching (Cohort 2).The median follow-up duration was 11.4 years. In Cohort 1 patients, mortality rates from non-liver-related diseases were 71.0% (22/31) in IFN-SVR patients, 34.9% (37/106) in IFN-non-SVR patients and 50.0% (248/496) in non-IFN patients respectively. In Cohort 2 patients, mortality rates from non-liver-related diseases were 72.2% (13/18) in IFN-SVR patients and 46.8% (29/62) in non-IFN patients respectively. The eradication of HCV reduced all-cause mortality (hazard ratio (HR), 0.265; 95% confidence interval (CI), 0.058-0.380) including non-liver-related mortality (HR, 0.439; 95% CI, 0.231-0.834) and the incidence of HCC (HR, 0.275; 95% CI, 0.156-0.448). CONCLUSIONS: Eradication of HCV reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV.

Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) can develop in patients with chronic hepatitis C after they have achieved a sustained virologic response (SVR) to antiviral therapy, that is eradication of hepatitis C virus (HCV). Thus, surveillance for HCC remains necessary after SVR. We investigated factors that are predictive of HCC in HCV-infected patients who achieved SVR. METHODS: The incidence and risk factors for HCC were evaluated in 522 patients who achieved SVR with interferon-based antiviral therapy for HCV. Patients maintained regular follow-up every 6 months for HCC surveillance. The FIB-4 index and aspartate aminotransferase to platelet count ratio index were calculated based on laboratory data at the time that SVR was documented (SVR24). RESULTS: Patients continued follow-up visits for 1.0-22.9 years (median, 7.2 years) after SVR. HCC developed in 18 patients. The incidence of HCC was 1.2% at 5 years and 4.3% at 10 years. The use of peginterferon or ribavirin for treatment and a history of antiviral therapy prior to the course when SVR was achieved were not associated with the incidence of HCC after SVR. The presence of diabetes mellitus (risk ratio 2.08; P = 0.0451) and FIB-4 index calculated at the time of SVR24 (risk ratio 1.73; P = 0.0198) were associated with a higher likelihood of HCC after SVR by multivariate analysis. CONCLUSIONS: Patients with diabetes mellitus and patients with the elevation of FIB-4 index at SVR24 are at higher risk of HCC after SVR. Surveillance for HCC should be continued in this patient subpopulation.

Impact of the branched-chain amino acid to tyrosine ratio and branched-chain amino acid granule therapy in patients with hepatocellular carcinoma: A propensity score analysis.

BACKGROUND AND AIM: It has been reported that the branched-chain amino acid (BCAA) to tyrosine ratio (BTR) is a useful indicator of liver function and BCAA therapy is associated with a decreased incidence of hepatocellular carcinoma (HCC). However, there has not been sufficient research on the relationship between BTR and the effects of BCAA therapy after initial treatment of HCC. We investigated the impact of BTR and BCAA therapy on survival in patients with HCC. METHODS: A total of 315 patients with HCC who were treated (n = 66) or not treated (n = 249) with BCAA were enrolled; of these, 66 were selected from each group using propensity score matching. Survival from liver-related mortality was analyzed. RESULTS: In patients who did not receive BCAA therapy (n = 249), multivariate analysis for factors associated with survival indicated that low BTR (≤ 4.4) was independently associated with poor prognosis in patients with HCC (hazard ratio, 1.880; 95% confidence interval, 1.125-3.143; P = 0.016). In addition, among patients selected by propensity score matching (n = 132), multivariate analysis indicated that BCAA therapy was independently associated with good prognosis in patients with HCC (hazard ratio, 0.524; 95% confidence interval, 0.282-0.973; P = 0.041). BTR was not significantly associated with survival. CONCLUSIONS: Intervention involving BCAA therapy improved survival in patients with HCC versus untreated controls, regardless of BTR. In addition, low BTR was associated with poor prognosis in patients who did not receive BCAA therapy.

Oral supplementation with branched-chain amino acid granules prevents hepatocarcinogenesis in patients with hepatitis C-related cirrhosis: A propensity score analysis.

AIM: It has been reported that branched-chain amino acids (BCAA) supplementation can improve nutritional status and reduce liver-related complications in patients with decompensated cirrhosis. BCAA supplementation reportedly reduces the incidence of hepatocellular carcinoma (HCC) in obese cirrhotic patients infected with hepatitis C virus (HCV). We investigated the effects of oral supplementation with BCAA granules on hepatocarcinogenesis in patients with HCV-related cirrhosis using propensity score matching. METHODS: A total of 60 patients with HCV-related cirrhosis and without history of HCC who were selected by one-to-one matching of propensity scores: 30 patients receiving 12 g/day of BCAA granules for 3 months or more (BCAA group) and 30 being observed without BCAA supplementation (control group). The impact of BCAA supplementation was analyzed on the incidence of HCC. RESULTS: The 3- and 5-year rates of HCC development were 13.7% and 13.7% in the BCAA group and 35.1% and 44.5% in the control group, respectively. The BCAA group had a significantly lower rate of HCC than the control group (P = 0.032). Multivariate analysis for factors that were associated with hepatocarcinogenesis indicated that BCAA supplementation was independently associated with a reduced incidence of HCC (hazard ratio 0.131; 95% confidence interval, 0.032-0.530; P = 0.004) along with sex and serum α-fetoprotein. Obesity (body mass index, ≥25 kg/m(2) ) was not significantly associated with an increased incidence of HCC. CONCLUSION: Oral supplementation with BCAA granules is associated with a reduced incidence of HCC in patients with HCV-related cirrhosis regardless of the presence of obesity based on the propensity score analysis.

[Case of small bowel angioectasia in which the resection site was angiographically detected using intraoperative dye infusion].

A 37-year-old Japanese man undergoing treatment for dilated cardiomyopathy was presented with weakness and melena. He had conjunctival pallor and difficulty in standing;his blood pressure was 81/62 mmHg. Abdominal computed tomography revealed contrast dye leakage into the small intestine. He was diagnosed with hemorrhagic shock secondary to intestinal bleeding;we administered large volumes of intravenous fluid along with performing a blood transfusion. We then performed angiography to determine the site of bleeding angioectasia and placed a catheter into the affected artery. We identified the resection site using an intraoperative dye infusion via the catheter, and successfully performed small bowel resection. He was subsequently discharged without complications.

A multi-institutional study designed by members of Tokyo Guidelines (TG) Core Meeting to elucidate the clinical characteristics and pathogenesis of acute cholangitis after bilioenteric anastomosis and biliary stent insertion with a focus on biliary obstruction: Role of transient hepatic attenuation difference (THAD) and pneumobilia in improving TG diagnostic performance.

BACKGROUND/PURPOSE: The aim of this study was to clarify the clinical characteristics of acute cholangitis (AC) after bilioenteric anastomosis and stent-related AC in a multi-institutional retrospective study, and validate the TG18 diagnostic performance for various type of cholangitis. METHODS: We retrospectively reviewed 1079 AC patients during 2020, at 16 Tokyo Guidelines 18 (TG 18) Core Meeting institutions. Of these, the post-biliary reconstruction associated AC (PBR-AC), stent-associated AC (S-AC) and common AC (C-AC) were 228, 307, and 544, respectively. The characteristics of each AC were compared, and the TG18 diagnostic performance of each was evaluated. RESULTS: The PBR-AC group showed significantly milder biliary stasis compared to the C-AC group. Using TG18 criteria, definitive diagnosis rate in the PBR-AC group was significantly lower than that in the C-AC group (59.6% vs. 79.6%, p < .001) because of significantly lower prevalence of TG 18 imaging findings and milder bile stasis. In the S-AC group, the bile stasis was also milder, but definitive-diagnostic rate was significantly higher (95.1%) compared to the C-AC group. The incidence of transient hepatic attenuation difference (THAD) and pneumobilia were more frequent in PBR-AC than that in C-AC. The definitive-diagnostic rate of PBR-AC (59.6%-78.1%) and total cohort (79.6%-85.3%) were significantly improved when newly adding these items to TG18 diagnostic imaging findings. CONCLUSIONS: The diagnostic rate of PBR-AC using TG18 is low, but adding THAD and pneumobilia to TG imaging criteria may improve TG diagnostic performance.

Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis.

BACKGROUND & AIMS: Some patients with chronic hepatitis B virus (HBV) infection progress to hepatocellular carcinoma (HCC). However, the long-term effect of nucleos(t)ide analogue (NA) therapy on progression to HCC is unclear. METHODS: Therefore, we compared chronic hepatitis B patients who received NA therapy to those who did not, using a propensity analysis. RESULTS: Of 785 consecutive HBV carriers between 1998 and 2008, 117 patients who received NA therapy and 117 patients who did not, were selected by eligibility criteria and propensity score matching. Factors associated with the development of HCC were analyzed. In the follow-up period, HCC developed in 57 of 234 patients (24.4%). Factors significantly associated with the incidence of HCC, as determined by Cox proportional hazards models, include higher age (hazard ratio, 4.36 [95% confidence interval, 1.33-14.29], p=0.015), NA treatment (0.28 [0.13-0.62], p=0.002), basal core promoter (BCP) mutations (12.74 [1.74-93.11], p=0.012), high HBV core-related antigen (HBcrAg) (2.77 [1.07-7.17], p=0.036), and high gamma glutamyl transpeptidase levels (2.76 [1.49-5.12], p=0.001). CONCLUSIONS: NA therapy reduced the risk of HCC compared with untreated controls. Higher serum levels of HBcrAg and BCP mutations are associated with progression to HCC, independent of NA therapy.

Association between hepatic steatosis and hepatic expression of genes involved in innate immunity in patients with chronic hepatitis C.

BACKGROUNDS/AIMS: We investigated the association between hepatic steatosis and hepatic expression of genes involved in innate immunity, both of which are reportedly associated with resistance to peginterferon (PEG-IFN) and ribavirin combination therapy for hepatitis C virus (HCV) infection. METHODS: A total of 122 patients infected with HCV genotype 1b who underwent and completed PEG-IFN and ribavirin combination therapy were studied. Hepatic steatosis was evaluated on the basis of the liver specimen biopsied prior to antiviral therapy. The levels of mRNA of innate immunity genes (RIG-I, MDA5, LGP2, Cardif, RNF125, ISG15, and USP18) were measured by real-time polymerase chain reaction in RNA extracted from biopsied liver tissue and compared between patients with and without hepatic steatosis. RESULTS: The proportion of patients with hepatic steatosis, the hepatic expression levels of RIG-I gene, and RIG-I/Cardif and RIG-I/RNF125 ratios were significantly higher in patients in whom serum HCV RNA did not disappear throughout the treatment period. Hepatic expression of RIG-I and the ratios of RIG-I/Cardif and RIG-I/RNF125 were significantly higher in patients with steatosis than those without. CONCLUSIONS: Changes in hepatic expression of some genes involved in innate immunity were observed along with hepatic steatosis, possibly playing a mechanistic role in resistance to IFN-based therapy in patients with hepatic steatosis.

Higher hepatic gene expression and serum levels of matrix metalloproteinase-2 are associated with steatohepatitis in non-alcoholic fatty liver diseases.

We investigated the gene expression of tissue inhibitor metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) and serum levels of TIMPs, MMPs, and hyaluronic acid that are associated with liver fibrosis in 64 patients with nonalcoholic fatty liver diseases (NAFLD). Whereas, no differences were found between patients with and without nonalcoholic steatohepatitis (NASH) in serum levels of hyaluronic acid when excluding NASH patients with advanced fibrosis, the quantity of MMP2 mRNA in liver tissue and serum MMP2 levels were significantly higher in patients with NASH than those without, even focusing on patients with less advanced fibrosis, indicating the initiation of liver fibrosis.

Characteristics of elderly hepatitis C virus-associated hepatocellular carcinoma patients.

BACKGROUND AND AIM: The average age of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) patients has been rising in Japan. We evaluate characteristics of HCV-positive patients who develop HCC in older age to determine an optimal surveillance strategy. METHODS: A total of 323 patients with three or more years of follow-up before HCC diagnosis and 323 propensity-matched controls without HCC were studied. HCC patients were classified into four groups according to age at the time of HCC diagnosis: group A (≤ 60 years, n = 36), group B (61-70 years, n = 115), group C (71-80 years, n = 143), and group D (> 80 years, n = 29). Clinical and laboratory data were compared. RESULTS: Platelet counts were significantly higher in the older groups at HCC diagnosis (P < 0.0001). The rate of platelet counts decline was lower in older groups (P = 0.0107). The average integration value of serum alanine aminotransferase (ALT) in groups A, B, C, and D were 80.9 IU/L, 62.3 IU/L, 59.0 IU/L, and 44.9 IU/L, respectively (P < 0.0001). In older patients (≥ 65 years old), cirrhosis and average integration value of ALT were significantly associated with hepatocarcinogenesis, but platelet count was not. CONCLUSION: Elderly HCV-positive patients (≥ 65 years old) with low ALT values developed HCC regardless of their platelet counts. These findings should be taken into account when designing the most suitable HCC surveillance protocol for this population.

JPN clinical practice guidelines 2021 with easy-to-understand explanations for the management of acute pancreatitis.

BACKGROUND: In preparing the Japanese (JPN) guidelines for the management of acute pancreatitis 2021, the committee focused the issues raised by the results of nationwide epidemiological survey in 2016 in Japan. METHOD: In addition to a systematic search using the previous JPN guidelines, papers published from January 2014 to September 2019 were searched for the contents to be covered by the guidelines based on the concept of GRADE system. RESULTS: Thirty-six clinical questions (CQ) were prepared in 15 subject areas. Based on the facts that patients diagnosed with severe disease by both Japanese prognostic factor score and contrast-enhanced computed tomography (CT) grade had a high fatality rate and that little prognosis improvement after 2 weeks of disease onset was not obtained, we emphasized the importance of Pancreatitis Bundles, which were shown to be effective in improving prognosis, and the CQ sections for local pancreatic complications had been expanded to ensure adoption of a step-up approach. Furthermore, on the facts that enteral nutrition for severe acute pancreatitis was not started early within 48 h of admission and that unnecessary prophylactic antibiotics was used in almost all cases, we emphasized early enteral nutrition in small amounts even if gastric feeding is used and no prophylactic antibiotics are administered in mild pancreatitis. CONCLUSION: All the members of the committee have put a lot of effort into preparing the extensively revised guidelines in the hope that more people will have a common understanding and that better medical care will be spread.

Modified Socratic Method (planned and executed by Takada) for medical education: Grade II Acute Cholecystitis of Tokyo Guidelines 2018 as an example case.

BACKGROUND: Socratic method, which is an educational method to promote critical thinking through a dialogue, has never been practiced in a large number of people at the academic societies. METHODS: Modified Socratic method was performed for the first time as an educational seminar using an example case of moderate acute cholecystitis based on the evidence described in Tokyo Guidelines 2018. We adopted a method that Takada had been modifying for many years: the instructor first knows the degree of recognition of the audience, then the instructor gives a lecture in an easy-to-understand manner and receives questions from the audience, followed by repeated questions and answers toward a common recognition. RESULTS: Using slides, video, and an answer pad, 281 participants including the audience, instructors and moderators came together to repeatedly ask and answer questions in the five sessions related to the case scenario. The recognition rate of the topic of Critical View of Safety increased significantly before vs after this method (53.0% vs 90.3%). The seminar had been successfully performed by receiving a lot of praise from the participants. CONCLUSION: This educational method is considered to be adopted by many academic societies in the future as an effective educational method.

Outcome in partial early virologic responders to combination therapy with peginterferon and ribavirin in patients infected with hepatitis C virus genotype 1b.

The course and outcome in patients infected with hepatitis C virus (HCV) genotype 1b with partial early virologic response during combination therapy with peginterferon and ribavirin, in whom serum HCV RNA is detectable but has decreased by more than 2 log(10) 12 weeks after the start of the therapy, has not been elucidated sufficiently. The outcome in this group of patients was investigated. Serum HCV RNA levels was measured every 4 weeks in 149 patients with HCV genotype 1b infection who underwent combination therapy for 48 weeks. In patients with partial early virologic response, the time point when serum HCV RNA became undetectable as well as the final virologic response to treatment was determined. Sixty-three patients (42.3%) had partial early virologic response. The time when serum HCV RNA became undetectable ranged from 16 to 48 weeks after the start of therapy. Serum HCV RNA remained detectable in 17 patients. The rates of sustained virologic response decreased with the delay of the time when serum HCV RNA became undetectable; sustained virologic responder was not found in patients in whom HCV RNA was still detectable at 24 weeks after the start of treatment. The degree of decrease in serum HCV RNA levels at 12 weeks corresponded to the rate of sustained virologic response in partial early virologic responders. The outcome of partial early virologic responders varied greatly, and close monitoring of serum HCV RNA is required for predicting the outcome of treatment in these patients.

[Ruptured aneurysm of a posterior inferior pancreaticoduodenal artery associated with duodenal stenosis after transcatheter arterial embolization].

We describe a 72-year-old man admitted to hospital as an emergency case of epigastric abdominal pain. CT scan visualized massive hemorrhage around the pancreatic head. Computed tomographic angiography showed stenosis at the origin of the celiac artery and a 10 mm aneurysm of the posterior inferior pancreaticoduodenal artery (PIPDA). An emergency angiogram revealed a long aneurysm in the PIPDA. The aneurysm had irregular width and was 75 mm in length. A gastroduodenal artery and the PIPDA were supplied from the superior mesenteric artery. A transcatheter arterial embolization (TAE) was performed. We reviewed 45 cases of pancreaticoduodenal aneurysms after 2000 and cases of the pancreaticoduodenal false aneurysms after 1972. As a result, we inferred that this case without pancreatitis or pancreas surgery was a true aneurysm made by the bloodstream changes caused by the celiac artery stenosis.

An early viral response to standard interferon-alpha identifies resistance to combination therapy with peginterferon and ribavirin in patients infected by HCV genotype 1.

As combination therapy with peginterferon (PEG-IFN) and ribavirin has a high morbidity, identifying individuals with hepatitis C virus (HCV) who will not respond to the treatment would be beneficial. The early responses of serum HCV RNA levels to standard interferon (IFN) and PEG-IFN were examined to determine if it was possible to identify resistance to combination therapy. One hundred thirty-one patients infected with HCV genotype 1b were enrolled. Patients were given 6 MU of standard IFN alpha-2b at least 2 weeks before initiating combination therapy. Serum HCV RNA levels were measured before, 24 hr after the administration of standard IFN, and 24 hr after the administration of PEG-IFN (at the start of the combination therapy). The association between reductions in HCV RNA levels at 24 hr after the administration of standard IFN and PEG-IFN and the outcome of combination therapy were analyzed. Reductions in HCV RNA levels were poorer in patients who did not respond than in those with a sustained virologic responses or relapses (P < 0.0001), both 24 hr after the administration of standard IFN and 24 hr after the administration of PEG-IFN. Reductions in HCV RNA levels 24 hr after the administration of standard IFN were an independent factor associated with non-response by multivariate analysis. An early reduction in viral load to a single administration of standard IFN is a useful predictor of non-response in patients with HCV genotype 1, allowing for pretreatment identification of patients who will not benefit from combination therapy.

Incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection who have normal alanine aminotransferase values.

The importance of alanine aminotransferase (ALT) levels in the progression of hepatitis B virus (HBV) infection remains a subject of debate. This study sought to identify independent risk factors involved in development of hepatocellular carcinoma (HCC), particularly in patients with chronic HBV infection who have normal ALT values. Data from 381 consecutive hepatitis B patients were analyzed with average ALT integration values < or = 40 IU/L and follow-up periods of > 3 years. Integration values were calculated from biochemical tests, and serological markers associated with the cumulative incidence of HCC were analyzed. HCC developed in 17 of the 381 patients (4.5%) during the follow-up period. Male sex (hazard ratio, 6.011 [95% confidence interval: 1.353-26.710], P = 0.018), high HBV-DNA levels (> or = 5.0 log copies/ml; 5.125 [1.880-13.973], P = 0.001), low platelet counts (< 15.0 x 10(4)/mm(3); 4.803 [1.690-13.647], P = 0.003), and low total cholesterol levels (< 130 mg/dl; 5.983 [1.558-22.979], P = 0.009) were significantly associated with greater incidence of HCC development. High HBV-DNA levels and low platelet counts are associated with the development of HCC in patients infected with hepatitis B who have normal ALT values. Therefore, maintenance of low HBV-DNA levels is important for the prevention of HCC in patients with low platelet counts, particularly in patients whose ALT values fall within the current normal range.

Impact of COVID-19 pandemic on surveillance of hepatocellular carcinoma: A study in patients with chronic hepatitis C after sustained virologic response.

Background: The current coronavirus disease 2019 (COVID-19) pandemic has strongly influenced many aspects of the medical care, including cancer surveillance. Aims: We investigated how the COVID-19 pandemic influenced surveillance for hepatocellular carcinoma (HCC), focusing on patients with hepatitis C virus infection who were receiving surveillance for HCC after sustained virologic response (SVR) in Japan. Methods: Patients who achieved SVR between 1995 and 2017 and continued receiving surveillance were compared by month in terms of the rate at which they kept their scheduled visits for HCC surveillance from July 2019 to May 2020. Results: The percentage of kept scheduled visits was above 97% before February 2020. By contrast, it declined sharply after March 2020 when COVID-19 became pandemic; the percentages were 75.5% in March, 63.0% in April and 49.1% in May 2020 (July 2019-February 2020 vs March-May 2020, P < 0.0001). Similar declines were observed in patients with cirrhosis or advanced fibrosis and in those with a history of HCC. Whereas most patients who cancelled a scheduled visit before February 2020 did not reschedule it, the majority of patients with cancellations after March 2020 did want to reschedule. Conclusions: The percentages of scheduled visits that were kept declined rapidly after COVID-19 became pandemic in Japan, although the spread of COVID-19 is relatively mild and the legal restriction of people's behaviour and movement is absent. Instituting measures to follow-up with cancelled patients and resume surveillance will be necessary in the future.