Risk Factors and Nomogram Model for Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients with Low-Level Viremia.

Background and aim: Patients with chronic hepatitis B patients (CHB) with low-level viremia (LLV) are not necessarily at low risk of developing hepatocellular carcinoma (HCC). The question of whether CHB patients with LLV require immediate antiviral agent (AVT) or long-term AVT remains controversial. The study aims to investigate the risk of HCC development and the risk factors in CHB patients with LLV and construct a nomogram model predicting the risk of HCC. Methods: We conducted a retrospective cohort study that enrolled 16,895 CHB patients from January 2008 to December 2020. The patients were divided into three groups for comparison: the LLV group, maintained virological response (MVR) group and HBV-DNA>2000 group. The cumulative incidence of progression to HCC was assessed. Cox regression analysis was performed to determine the final risk factors, and a nomogram model was constructed. The 10-fold Cross-Validation method was utilized for internal validation. Results: A total of 408 new cases of HCC occurred during the average follow-up period of 5.78 years. The 3, 5, and 10-year cumulative HCC risks in the LLV group were 3.56%, 4.96%, and 9.51%, respectively. There was a significant difference in the cumulative risk of HCC between the HBV-DNA level > 2000 IU/mL and LLV groups (p = 0.049). Independent risk factors for HCC development in LLV group included male gender, age, presence of cirrhosis, and platelets count. The Area Under the Curve (AUC) values for the 3-year and 5-year prediction from our HCC risk prediction model were 0.75 and 0.76, respectively. Conclusion: Patients with LLV and MVR are still at risk for developing HCC. The nomogram established for CHB patient with LLV, incorporating identified significant risk factors, serves as an effective tool for predicting HCC-free outcomes. This nomogram model provides valuable information for determining appropriate surveillance strategies and prescribing AVT.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy.

BACKGROUND/AIMS: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. METHODS: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan's cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray's cumulative incidence and Cox subdistribution hazards models to analyze HCC development. RESULTS: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. CONCLUSION: Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

INTRODUCTION: Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). METHODS: The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. RESULTS: A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. CONCLUSION: Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Cholestatic Hepatitis with Concomitant Nephrotic Syndrome due to Secondary Syphilis in a Young Man.

Introduction: Syphilis, an ancient sexually transmitted disease, is recognized as a systemic infection disease manifesting with diverse symptoms and variations. Secondary syphilis characterized by systemic symptoms resulted from hematogenous and lymphatic dissemination of the infection, may include manifestations such as hepatitis and nephrotic syndrome. However, the simultaneous occurrence of hepatitis and nephrotic syndrome in secondary syphilis is rare. Case Presentation: A young man presented with fatigue, abnormal liver function tests, and hyperbilirubinemia and had history of men who have sex with men (MSM). Serological tests confirmed the diagnosis of secondary syphilis, and kidney biopsy indicated membranous nephritis. After antibiotic treatment, the patient experienced resolution of proteinuria, and liver enzyme levels returned to normal. Conclusion: Syphilis should be considered in the differential diagnosis of simultaneous liver and kidney dysfunction, particularly in patients engaging in high-risk sexual behavior. This case highlights the importance of considering syphilis in young patients with MSM and presenting with unexplained nephrotic syndrome and liver abnormalities.

The Efficacy of On-Site Integration Screening and Microelimination Programs for Chronic Hepatitis C in a Detection Center: A Comparison of the Treatment Outcomes and Characteristics of Incarcerated Patients and Outpatients.

We aimed to analyze the different patient characteristics and treatment outcomes (such as sustained viral response, SVR) between incarcerated patients with chronic hepatitis C (CHC) and those with CHC from the outpatient department through an on-site integrated screening and microelimination program in a detection center. In this retrospective study, which ran from May 2021 to April 2022, we included 32 consenting male prisoners aged at least 20 years who were willing to participate in the study. Members of the control group (who received DAAs in an outpatient setting) were selected from the treated CHC patient databank of individuals who received DAA regimens at Chi Mei Hospital between January 2021 and December 2022. The patients in the two groups did not differ significantly in terms of age, FIB-4 score, HCV RNA, HBV coinfection, hemogram findings, coagulation profiles, and renal function tests. However, the patients in the incarcerated group had a significantly different genotype distribution compared to the control group, significantly lower liver enzyme levels, and higher albumin and bilirubin levels compared to those in the control group. The rate of SVR to DAA treatment obtained among incarcerated patients did not differ significantly from that obtained among patients in the control group. Loss to follow-up (for several reasons) is a major reason for treatment discontinuation among these patients.

An algorithm for simplified hepatitis C virus treatment with non-specialist care based on nation-wide data from Taiwan.

BACKGROUND: Both European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) guidelines recommend simplified hepatitis C virus (HCV) treatment with pan-genotypic sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for eligible patients. This observational study used real-world data to assess these regimens' safety in eligible patients and develop an algorithm to identify patients suitable for simplified treatment by non-specialists. METHODS: 7,677 HCV-infected patients from Taiwan Hepatitis C Registry (TACR) who received at least one dose of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, and fulfilled the EASL/AASLD-IDSA criteria for simplified treatment were analyzed. Multivariate analysis was conducted on patient characteristics and safety data. RESULTS: Overall, 92.8% (7,128/7,677) of patients achieved sustained virological response and only 1.9% (146/7,677) experienced Grades 2-4 laboratory abnormalities in key liver function parameters (alanine aminotransferase, aspartate aminotransferase, and total bilirubin), with only 18 patients (0.23%) experiencing Grades 3-4 abnormalities. Age > 70 years old, presence of hepatocellular carcinoma, total bilirubin > 1.2 mg/dL, estimated glomerular filtration rate < 60 mL/min/1.73 m2, and Fibrosis-4 > 3.25 were associated with higher risks of Grades 2-4 abnormalities. Patients with any of these had an odds of 4.53 times than that of those without in developing Grades 2-4 abnormalities (p < 0.01). CONCLUSIONS: Real-world data from Taiwan confirmed that simplified HCV treatment for eligible patients with pan-genotypic regimens is effective and well tolerated. The TACR algorithm, developed based on this study's results, can further identify patients who can be safely managed by non-specialist care.

Artificial intelligence predicts direct-acting antivirals failure among hepatitis C virus patients: A nationwide hepatitis C virus registry program.

BACKGROUND/AIMS: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1-3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. METHODS: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. RESULTS: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. CONCLUSION: Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

A therapeutic dose and its pharmacokinetics of ropeginterferon Alfa-2b for hepatitis C treatment.

AIM: Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. Its biweekly dosing schema has demonstrated tolerability and clinical efficacy for treating chronic hepatitis in previous clinical studies. This trial evaluates the pharmacokinetics of 400 µg ropeginterferon alfa-2b in patients with chronic hepatitis C virus (HCV) and provides the data to support the clinical utility of ropeginterferon alfa-2b at 400 µg. METHODS: Seventeen patients with chronic HCV genotype 2 were enrolled to receive a single injection of 400 µg ropeginterferon alfa-2b plus 14-day treatment of ribavirin. Pharmacokinetics, safety, and HCV RNA reduction/clearance were assessed. RESULTS: Tmax was 154.003 h and T1/2 was 114.273 h. The Cmax was 29.823 ng mL-1. AUClast was 9364.292 h∗ng mL-1 and AUCinf was 11084.317 h∗ng mL-1. All adverse events were mild or moderate, and there were no serious adverse events. A 1000-fold reduction in the geometric mean of HCV RNA was observed 14 d after the single injection of ropeginterferon alfa-2b. Two patients achieved clearance of HCV RNA, and the other five patients had HCV RNA levels lower than 200 IU mL-1. CONCLUSION: Ropeginterferon alfa-2b at 400 µg led to PK exposures associated with safety and notable clinical activity in patients with chronic HCV. This study suggests that ropeginterferon alfa-2b at 400 µg is an acceptable dosing regimen for treating chronic HCV and also provides supporting data for the clinical use of ropeginterferon alfa-2b at a higher starting dose for other indications.

Clinical significance of abdominal computed tomography and colonoscopy in the evaluation of phlebosclerotic colitis.

Clinical manifestations of phlebosclerotic colitis (PC) exhibit significant variability, necessitating diverse treatment strategies depending on disease severity. However, there is limited research exploring the relationship between imaging findings and disease severity. Hence, this retrospective study aimed to analyze the correlation between computed tomography (CT) findings, colonoscopic features, and disease severity. This study compared the abdominal CT characteristics, colonoscopy findings, and treatment modalities of 45 PC patients. CT images were assessed for the severity of mesenteric venous calcification, maximum colonic wall thickness, number of involved colonic segments, and presence of pericolic inflammation. Colonoscopic images were assessed for dark purple discoloration mucosa, erosive and ulcerative lesions, mucosal edema, luminal narrowing, and the number of involved colonic segments. In addition, patients were categorized into three groups: the observation (n = 15), medical treatment (n = 19), and operation (n = 11) groups. In CT images, a significant difference in pericolic inflammation (p = 0.039) was observed among groups. Further, significant differences in dark purple discoloration mucosa (p = 0.033), erosive or ulcerative lesions (p < 0.001), mucosal edema (p < 0.001), luminal narrowing (p = 0.012), and the number of involved colonic segments (p = 0.001) were observed in colonoscopy. Moreover, we found positive correlations between CT and colonoscopy features. In conclusion, CT manifestations and colonoscopy findings exhibited correlation with disease severity in PC. When limited to one diagnostic tool, observations from that tool can infer potential manifestations of the alternative tool.

Body weight increase and metabolic derangements after tenofovir disoproxil fumarate switch to tenofovir alafenamide in patients with chronic hepatitis B.

BACKGROUND: Lipid-lowering effect was observed during treatment with tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB). However, the metabolic features in patients switching from TDF to tenofovir alafenamide (TAF) remain unclear. AIMS: To compare the impacts of switching from TDF to TAF or from entecavir to TAF on body weight and metabolic features in patients with CHB. METHODS: This was a multi-centre, prospective, observational study in patients with CHB on TDF or entecavir who switched to TAF. Baseline characteristics, lipid profile and sugar profile were determined. This study received IRB approval from each hospital. RESULTS: We enrolled 177 patients on TDF (99) or entecavir (78) and followed them for 48 weeks after the switch to TAF. At baseline, TDF-experienced patients had lower serum triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol than entecavir-experienced patients. The switch from TDF to TAF significantly increased body weight, triglyceride, total cholesterol, HDL, LDL, fasting glucose, glycaemic haemoglobin, insulin and insulin resistance. The switch from entecavir to TAF did not affect these measures. There was no significant difference in atherosclerotic cardiovascular disease risk scores between groups. CONCLUSIONS: The switch from TDF to TAF was associated with weight gain, derangements of lipid profile, and increased insulin resistance in patients with CHB. Long-term effects on these metabolic features need further investigation.

Manipulating Diastereomeric Bicyclononynes to Sensitively Determine Enzyme Activity and Facilitate Macromolecule Conjugations.

Bicyclo[6.1.0]nonyne (BCN) is one of the most commonly used cycloalkynes in strain-promoted azide-alkyne cycloaddition (SPAAC). The synthesis of BCN produces two diastereomers, exo-BCN and endo-BCN. The potential significance of the different steric structures of the tricyclic fused rings in SPAAC products synthesized from the BCN diastereomers has not been previously studied. We first demonstrated that only endo-BCN could reduce the level of fluorescence quenching in SPAAC reaction products. The reduction was likely due to the presence of extended tricyclic fused ring systems. This hypothesis was supported by the synthesis of a fluorescence always-on construct by substituting endo-BCN for exo-BCN in a previously reported chemical probe that was characterized with good contact fluorescence quenching. We also synthesized bis-BCN derivatives to enhance the steric structural differences in the corresponding SPAAC products. A constitutional isomer of the azido-derivatized 5(6)-carboxyfluorescein [5(6)-FAM] was reacted with both bis-exo-BCN and bis-endo-BCN compounds. However, one form of the bis-exo-BCN-based product did not augment contact fluorescence quenching, while a second bis-exo-BCN product could not further reduce contact fluorescence quenching. Nevertheless, a new fluorescence turn-on chemical probe was employed to determine the activities of two serum biomarkers, butyrylcholinesterase and paraoxonase 1. Moreover, bis-endo-BCN was exploited to successfully conjugate BSA with a 5-FAM derivative compound.

The mortality of hospitalized patients with COVID-19 and non-cirrhotic chronic liver disease: a retrospective multi-center study.

Background: Patients with chronic liver disease (CLD) have a higher risk of mortality when infected with severe acute respiratory syndrome coronavirus 2. Although the fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and albumin-bilirubin grade (ALBI) score can predict mortality in CLD, their correlation with the clinical outcomes of CLD patients with coronavirus disease 2019 (COVID-19) is unclear. This study aimed to investigate the association between the liver severity and the mortality in hospitalized patients with non-cirrhotic CLD and COVID-19. Methods: This retrospective study analyzed 231 patients with non-cirrhotic CLD and COVID-19. Clinical characteristics, laboratory data, including liver status indices, and clinical outcomes were assessed to determine the correlation between liver status indices and the mortality among patients with non-cirrhotic CLD and COVID-19. Results: Non-survivors had higher levels of prothrombin time-international normalized ratio (PT-INR), alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein (hs-CRP) and lower albumin levels. Multivariable analysis showed that ALBI grade 3 (odds ratio (OR): 22.80, 95% confidence interval (CI) [1.70-305.38], p = 0.018), FIB-4 index ≥ 3.25 (OR: 10.62, 95% CI [1.12-100.31], p = 0.039), PT-INR (OR: 19.81, 95% CI [1.31-299.49], p = 0.031), hs-CRP (OR: 1.02, 95% CI [1.01-1.02], p = 0.001), albumin level (OR: 0.08, 95% CI [0.02-0.39], p = 0.002), and use of vasopressors (OR: 4.98, 95% CI [1.27-19.46], p = 0.021) were associated with the mortality. Conclusion: The ALBI grade 3 and FIB-4 index ≥ 3.25, higher PT-INR, hsCRP levels and lower albumin levels could be associated with mortality in non-cirrhotic CLD patients with COVID-19. Clinicians could assess the ALBI grade, FIB-4 index, PT-INR, hs-CRP, and albumin levels of patients with non-cirrhotic CLD upon admission.

Lymphocyte-Rich Hepatocellular Carcinoma with Multiple Lymphadenopathy and Positive Epstein-Barr Virus Encoding Region.

Lymphocyte-rich hepatocellular carcinoma (HCC) represents the rarest subtype among the various subgroups of HCC, and limited clinical data are available for this particular subtype. It is commonly observed as a solitary lesion and tends to present at an early stage. Histopathological examination typically reveals tumor cells infiltrated by a lymphocyte-rich background, leading to its designation as lymphoepithelioma-like HCC. Unlike other lymphoepithelioma-like tumors associated with the Epstein-Barr virus (EBV), lymphocyte-rich HCC is predominantly negative for EBV. This subtype is characterized by more favorable clinical outcomes and prognosis compared to conventional HCC. Here, we present a case of lymphocyte-rich hepatocellular carcinoma (HCC) characterized by the presence of bilateral hepatic tumors and concurrent multiple lymphadenopathy. Interestingly, contrary to previous literature, the examination for the Epstein-Barr virus (EBV) revealed a positive result in this particular case.

Effectiveness and safety of 8-week glecaprevir/pibrentasvir in HCV treatment-naïve patients with compensated cirrhosis: real-world experience from Taiwan nationwide HCV registry.

BACKGROUND: Large-scale real-world data of the 8-week glecaprevir/pibrentasvir (GLE/PIB) therapy for treatment-naïve patients of chronic hepatitis C virus (HCV) infection with compensated cirrhosis is scarce. METHODS: The TASL HCV Registry (TACR) is an ongoing nationwide registry program that aims to set up a database and biobank of patients with chronic HCV infection in Taiwan. In this study, data were analyzed as of 31 October 2021 for treatment-naïve HCV patients with compensated cirrhosis receiving 8-week GLE/PIB therapy. Effectiveness reported as sustained virologic response at off-therapy week 12 (SVR12) and safety profiles were assessed. Patient characteristics potentially related to SVR12 were also evaluated. RESULTS: Of the 301 patients enrolled, 275 had available SVR12 data. The SVR12 rate was 98.2% (270/275) in the modified intention-to-treat (mITT) population and 89.7% (270/301) in the ITT population. For those mITT patients with genotype 3, FibroScan > 20 kPa, platelet < 150,000/µl, and FibroScan > 20 kPa and platelet < 150,000/µl, the SVR12 rates were 100% (6/6), 100% (12/12), 98.0% (144/147), 100% (7/7), respectively. Overall, 24.9% (75/301) patients experienced adverse events (AEs). The most frequent AEs (> 5%) included fatigue (9.0%) and pruritus (7.0%). Seven (2.3%) patients experienced serious AEs and two (0.7%) resulted in permanent drug discontinuation. None of them were considered as GLE/PIB-related. CONCLUSIONS: In this large-scale real-world Taiwanese cohort, 8-week GLE/PIB therapy was efficacious and well tolerated for treatment-naïve compensated cirrhosis patients. SVR12 rates were similarly high as in the clinical trials, including those with characteristics of advanced liver disease.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan.

BACKGROUND & AIMS: Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. METHODS: Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. RESULTS: Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. CONCLUSIONS: Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR. IMPACT AND IMPLICATIONS: The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

Iatrogenic Kaposi sarcoma of the small bowel in Crohn's disease following short-term use of immunomodulators: a case report and review of the literature.

BACKGROUND: Kaposi sarcoma is a vascular tumor highly related to human herpesvirus-8 and Kaposi sarcoma-associated herpesvirus. Kaposi sarcoma usually manifests as skin or mucosal lesions; involvement in visceral organs such as the gastrointestinal tract is rare. Kaposi sarcoma can occur in immunocompromised patients receiving immunosuppressive therapy, in which case it is known as iatrogenic Kaposi sarcoma or drug-induced Kaposi sarcoma. Intestinal Kaposi sarcoma in patients with inflammatory bowel disease is extremely rare. CASE PRESENTATION: A 46-year-old East Asian male with recently diagnosed Crohn's disease was administered azathioprine and prednisolone; however, the patient complained of persistent abdominal pain and diarrhea following treatment. Endoscopy revealed small bowel Kaposi sarcoma. The patient was treated with systemic chemotherapy successfully without relapse. CONCLUSIONS: This is the fifth case of Kaposi sarcoma developed over the small intestine in a patient with Crohn's disease following administration of immunomodulators. Additionally, this case indicated that even short-term immunomodulator use can induce Kaposi sarcoma in patients with inflammatory bowel disease. Thus, in patients with inflammatory bowel disease, if symptoms are aggravated or do not abate after immunomodulators prescription, and before intending to upgrade immunomodulators, endoscopy should be considered. Finally, chemotherapy can also be considered if both medication withdrawal and surgical intervention are not feasible.

A Phase 3 clinical trial validating the potency and safety of an innovative, extra-long-acting interferon in chronic hepatitis C.

Background and Aim: Ropeginterferon alfa-2b is a novel mono-pegylated, extra-long-acting interferon. It is administered infrequently and showed good tolerability and clinical activity for the chronic hepatitis B or C treatment in our previous Phase 2 clinical trials. This study aims to validate the potency and safety of this novel agent in a Phase 3 chronic viral hepatitis setting. Methods: Patients with chronic hepatitis C genotype 2 were randomized to receive subcutaneous injections of ropeginterferon alfa-2b biweekly or the conventional pegylated interferon alfa-2b weekly for 24 weeks, combined with ribavirin. The primary endpoint was to assess the safety and antiviral potency of ropeginterferon alfa-2b by the non-inferiority in sustained virologic response at 12 weeks after treatment. Results: A total of 222 patients were enrolled. Ropeginterferon alfa-2b group showed a favorable safety profile. Side effects that were generally associated with prior interferon therapies, including neutropenia, asthenia, fatigue, alopecia, dizziness, decreased appetite, nausea, flu-like symptoms including myalgia, pyrexia, and headache, and administration site reactions, were notably less in the ropeginterferon alfa-2b group. The cumulative incidence of adverse events of special interest was also notably higher in the control group. The primary endpoint was met and ropeginterferon alfa-2b showed a better SVR12 rate of 79.8% than 71.9% of the control group. Conclusion: Ropeginterferon alfa-2b is efficacious and has a favorable safety profile as compared with the conventional pegylated interferon alfa-2b. This study together with previous Phase 2 data validated ropeginterferon alfa-2b to be a new treatment option for chronic hepatitis C genotype 2.

Comparison of the risk of gastrointestinal perforation between patients with and without rheumatoid arthritis: A nationwide cohort study in Asia.

Objectives: Patients with rheumatoid arthritis (RA) may have an increased risk for gastrointestinal perforation (GIP) caused by medications or chronic inflammation. However, the risk of GIP between patients with and without RA remains unclear. Therefore, we conducted this study to clarify it. Methods: Using the Taiwan National Health Insurance Research Database, we identified patients with and without RA matched at 1:1 ratio by age, sex, and index date between 2000 and 2013 for this study. Comparison of the risk of GIP between the two cohorts was performed by following up until 2014 using Cox proportional hazard regression analyses. Results: In total, 11,666 patients with RA and an identical number of patients without RA were identified for this study. The mean age (±standard deviation) and female ratio were 55.3 (±15.2) years and 67.6% in both cohorts. Patients with RA had a trend of increased risk for GIP than patients without RA after adjusting for underlying comorbidities, medications, and monthly income [adjusted hazard ratio (AHR) 1.42; 95% confidence interval (CI) 0.99-2.04, p = 0.055]. Stratified analyses showed that the increased risk was significant in the female population (AHR 2.06; 95% CI 1.24-3.42, p = 0.005). Older age, malignancy, chronic obstructive pulmonary disease, and alcohol abuse were independent predictors of GIP; however, NSAIDs, systemic steroids, and DMARDs were not. Conclusion: RA may increase the risk of GIP, particularly in female patients. More attention should be paid in female population and those with independent predictors above for prevention of GIP.

Risk stratification of hepatocellular carcinoma incidence using a fibrosis-4-based prediction model in patients with chronic hepatitis C receiving antiviral therapy: a nationwide real-world Taiwanese cohort study.

A total of 1,589 patients who had received interferon-based treatment were enrolled and analyzed for the risk of hepatocellular carcinoma (HCC) in a real-world nationwide Taiwanese chronic hepatitis C cohort (T-COACH). We aimed to stratify HCC risk by non-invasive fibrosis index-based risk model. Of 1589 patients, 1363 (85.8%) patients achieved sustained virological response (SVR). Patients with SVR had 1, 3, 5 and 10-year cumulative HCC incidence rates of 0.55%, 1.87%, 3.48% and 8.35%, respectively. A Cox proportional hazards model revealed that non-SVR (adjusted hazard ratio [aHR]: 1.92, 95% confidence interval [CI]: 1.19-3.12, p = 0.008), diabetes mellitus (aHR: 2.11, 95% CI: 1.25-3.55, p = 0.005), and fibrosis (FIB)-4 at the end of follow-up (EOF; aHR: 5.60, 95% CI: 2.97-10.57, p < 0.0001) were independent predictors of HCC. Risk score models based on the three predictors were developed to predict HCC according to aHR. In model 1, the 10-year cumulative incidence rates of HCC were 43.35% in patients at high risk (score 9-10), 25.48% in those at intermediate risk (score 6-8), and 4.06% in those at low risk (score 3-5) of HCC. In model 2, the 10-year cumulative incidence rates of HCC were 39.64% in patients at high risk (at least two risk predictors), 19.12% in those at intermediate risk (with one risk predictor), and 2.52% in those at low risk (without any risk predictors) of HCC. The FIB-4-based prediction model at EOF could help stratify the risk of HCC in patients with chronic hepatitis C after antiviral treatment.