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

Backgrounds and Aim: Chronic hepatitis C (CHC) patients who fail antiviral therapy have a high risk of developing hepatocellular carcinoma (HCC). We investigated the effects of metformin and statins, commonly used to treat diabetes mellitus (DM) and hyperlipidemia (HLP), on HCC risk in CHC patients who failed antiviral therapy. Methods: CHC patients with failed interferon-based therapy were enrolled in a large-scale multicenter cohort study in Taiwan (T-COACH). HCC occurrence 1.5 years after the end of antiviral therapy was identified by linking to the cancer registry databases from 2003 to 2019. After considering death and liver transplantation as competing risks, Gray's cumulative incidence and Cox sub-distribution hazards for HCC development were used. Results: Among the 2,779 CHC patients, 480 (17.3%) developed new-onset HCC and 238 (8.6%) died after antiviral therapy. Metformin non-users with DM had a 51% higher risk of liver cancer than patients without DM, while statin users with HLP had a 50% lower risk of liver cancer than patients without HLP. The 5-year cumulative incidence of HCC was 16.5% in metformin non-users, significantly higher in metformin non-users than in patients without DM (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Conversely, HLP statin users had a significantly lower HCC risk than patients without HLP (3.8% vs. 12.5%; aSHR=0.50; P<0.001). Notably, the unfavorable effect of non-metformin use on increased HCC risk was mainly observed among patients without cirrhosis but not in patients with cirrhosis. In contrast, a favorable effect of statins reduced the risk of HCC in both cirrhotic and non-cirrhotic patients. Conclusion: Metformin for DM and statins for HLP have chemopreventive effects on HCC risk in CHC patients who failed antiviral therapy. These findings emphasize the importance of personalized preventive strategies for managing patients with these clinical profiles.

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.

Chronic Hepatitis C Virus Infection: An Ongoing Challenge in Screening and Treatment.

With the advent of direct-acting antiviral agents (DAA) in the recent few years, hepatitis C virus (HCV) infection has become a curable infectious disease. Successful clearance of HCV could lead to improvement of both hepatic and extrahepatic outcomes, such as complications of cirrhosis, hepatocellular carcinoma, cardiovascular diseases, and incident diabetes. However, challenges persist in reaching the HCV elimination goals of the World Health Organization by 2030. Among these challenges are identifying those already infected or undiagnosed subjects, re-linking to the care of known but untreated HCV-infected subjects, and developing strategies to enhance treatment rates and compliance in specific or high-risk populations. In addition, issues of post-DAA viral clearance, including avoiding or preventing reinfection in high-risk populations and surveillance of hepatocellular carcinoma, are important to consolidate the treatment's short- and long-term efficacies. In the current DAA era, treatment is the most effective prevention strategy not only in its excellent efficacy and safety but also in preventing HCV spread. All of the surveillance or measures should center on DAA treatment in clinical practice.

Reversibility of some oxidative stress markers in chronic hepatitis C patients after receiving direct-acting antiviral agents.

Introduction: Hepatitis C (HCV) is associated with extra-hepatic involvment, morbidity as well as metabolic changes. Whether these might be reversible if sustained virologic response (SVR) is achieved by direct-acting antiviral (DAA) therapy remains unknown. Methods: Chronic hepatitis C (CHC) individuals receiving DAA treatment with SVR were compared to those who underwent spontaneous clearance (SC) of HCV infection at the 2-year follow-up. Plasma oxidative stress markers (oxidized low-density lipoprotein (oxLDL), 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA) and ischemia-modified albumin (IMA)) as well as progression of liver fibrosis were evaluated. Results: Compared to SC individuals, those in the CHC group exhibited at baseline higher levels of oxLDL, 8-OHdG and IMA but not of MDA. In the SC group, 8-OHdG levels were elevated at 2-year post-SVR (p = 0.0409), while the DAA-treated CHC group showed decrease in oxLDL (p < 0.0001) and 8-OHdG (p = 0.0255) levels, approaching those of the SC group, but increased MDA (p = 0.0055) levels. Additionally, oxLDL levels were positively correlated with liver stiffness measurements at SVR (p = 0.017) and at 1 year post- SVR (p = 0.002). Conclusions: Plasma oxLDL showed post-SVR normalization after clearance of HCV viremia with DAAs and was associated with levels of hepatic fibrosis.

Interdependence of glycemic and lipid modulation in cured chronic hepatitis C patients by direct-acting antiviral agents.

BACKGROUND: Chronic hepatitis C virus (HCV) infection causes various liver diseases and metabolic disorders. With direct-acting antiviral agents (DAAs), which effectively eradicate pan-genotypic HCV, hepatic and concomitant metabolic restorations are achieved. The study aims to evaluate the posttherapeutic benefits of lipid and glycemic homeostasis. METHODS: Nighty-five chronic hepatitis C patients who achieved sustained virological response (SVR) by using DAAs were enrolled to collect plasma samples and fractionated lipoproteins at baseline, SVR, and during the post-SVR follow-ups for 6 months (pS6m) and 1 year (pS1yr). The lipid and glycemic parameters were analyzed to establish muturally modulatory relationships. RESULTS: Plasma cholesterol (Chol) and glucose were elevated at SVR from baseline, whereas plasma Chol remained increased until pS1yr; however, glucose returned to the basal level. The post-SVR responses included a peak elevation of glycated hemoglobin at pS6m, a sustained elevation of triglyceride (Tg), and sustained declines in insulin, homeostasis model assessment (HOMA)-insulin resistance, and HOMA-beta levels until pS1yr. The changes in plasma Chol and high-density-lipoprotein Chol showed positive correlations, as did the plasma Tg with low-density-lipoprotein Tg and very-low-density-lipoprotein Tg per particle load. Very-low-density-lipoprotein was found to be loaded with increased Tg and Chol and underwent efficient Tg catabolism in the form of conversion into low-density-lipoprotein. Additionally, the posttherapeutic dynamics exhibited correlations of high-density-lipoprotein Chol with plasma glucose and HOMA-beta. CONCLUSION: Irrespective of the baseline metabolic status, the posttherapeutic interdependent modulation of blood glycemic and lipid metabolic parameters were revealed in chronic hepatitis C patients following clearance of HCV viremia by DAA treatment.

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.

Higher Risk of Tumor Recurrence in NASH-Related Hepatocellular Carcinoma Following Curative Resection.

The outcomes for patients with NASH-related HCC after curative resection have not been clarified. This study compared the overall survival (OS), time-to-tumor recurrence (TTR), and recurrence-free survival (RFS) associated with NASH-related HCC and virus-related HCC after resection. Methods: Patients with HCC who underwent curative resection were retrospectively enrolled. Baseline characteristics, including disease etiologies and clinical and tumor features, were reviewed. The primary outcomes were OS, TTR, and RFS. Results: Two hundred and six patients were enrolled (HBV: n = 121, HCV: n = 54, NASH: n = 31). Of those with virus-related HCC, 84.0% achieved viral suppression. In both the overall and propensity-score-matched cohorts, those with NASH-related HCC experienced recurrence significantly earlier than those with virus-related HCC (median TTR: 1108 days vs. non-reached; p = 0.03). Through multivariate analysis, NASH-related HCC (hazard ratio (HR), 2.27; 95% confidence interval (CI), 1.25-4.12) was independently associated with early recurrence. The unadjusted RFS rate of the NASH-related HCC group was lower than the virus-related HCC group. There was no difference in the OS between the two groups. Conclusions: NASH-related HCC was associated with earlier tumor recurrence following curative resection compared to virus-related HCC. Post-surgical surveillance is crucial for detecting early recurrence in patients with NASH-related HCC.

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.

Concealable physically unclonable function chip with a memristor array.

A physically unclonable function (PUF) is a creditable and lightweight solution to the mistrust in billions of Internet of Things devices. Because of this remarkable importance, PUF need to be immune to multifarious attack means. Making the PUF concealable is considered an effective countermeasure but it is not feasible for existing PUF designs. The bottleneck is finding a reproducible randomness source that supports repeatable concealment and accurate recovery of the PUF data. In this work, we experimentally demonstrate a concealable PUF at the chip level with an integrated memristor array and peripherals. The correlated filamentary switching characteristic of the hafnium oxide (HfOx)-based memristor is used to achieve PUF concealment/recovery with SET/RESET operations efficiently. PUF recovery with a zero-bit error rate and remarkable attack resistance are achieved simultaneously with negligible circuit overhead. This concealable PUF provides a promising opportunity to build memristive hardware systems with effective security in the near future.

Real-world effectiveness and safety of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for genotype 6 chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) genotype 6 mainly distributes in Southeast Asia and South China. Because of the low prevalence in developed countries, optimal treatment for HCV genotype 6 in real-world setting remains to be determined. We aimed to evaluate the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV genotype 6 infection in Taiwan. METHODS: A total of 286 patients with chronic hepatitis C (CHC) genotype 6, 161 receiving 12-week SOF/VEL and 125 receiving 8-week GLE/PIB, were enrolled. All patients were followed up for 12 weeks after treatment completion. Demographic information, HCV viral load (VL), profiles of lipid and sugar, and adverse events were recorded and reviewed. RESULTS: Sustained virological response (SVR) rates of SOF/VEL and GLE/PIB evaluated by intention-to-treat analysis were 99.38% and 100%, respectively. SVR achieved 100%, regardless of cirrhosis or viral load (cutoff: 6 MIU/mL), of both regimens by per-protocol analysis. Skin itching was the most common adverse event, with an overall incidence of 6.64% which was more prevalent in GLE/PIB (12.0%) than SOF/VEL (2.48%). A significant decrease in the estimated glomerular filtration rate was observed in patients receiving SOF/VEL but not in those receiving GLE/PIB at the time of SVR. No patient discontinued treatment due to adverse event. CONCLUSION: The high SVR and excellent safety of SOF/VEL and GLE/PIB in real-world setting reveals that the two DAA regimens are favorable options for treatment of HCV genotype 6 in Taiwan and Asia.

Entecavir Prevents HBV Reactivation During Direct Acting Antivirals for HCV/HBV Dual Infection: A Randomized Trial.

BACKGROUND & AIMS: A strategy to prevent hepatitis B virus (HBV) virologic reactivation (HBVr) and clinical reactivation (CR) during direct acting antiviral (DAA) treatment of hepatitis C virus (HCV)/HBV dual infection remains an unresolved issue. METHODS: Noncirrhotic patients with dual HCV/HBV infection were enrolled and allocated randomly to 1 of 3 groups as follows: 12 weeks of DAA alone (group 1), 12 weeks of DAA plus 12 weeks of entecavir (group 2), or 12 weeks of DAA plus 24 weeks of entecavir (group 3). The entire study duration was 72 weeks. The primary end point was the occurrence of HBVr (defined by an increase of HBV DNA level >10-fold with quantifiable HBV DNA at baseline or the presence of HBV DNA with prior unquantifiable HBV DNA) and CR (defined by serum alanine aminotransferase level >2-fold the upper limit of normal in addition to HBVr). RESULTS: Fifty-six patients were allocated randomly as follows: 20 patients in group 1, 16 patients in group 2, and 20 patients in group 3. In group 1, HBV DNA levels increased significantly as early as 4 weeks after initiation of DAA and persisted until the end of the study. During DAA treatment, HBVr occurred in 50% in group 1 vs 0% in group 2 and 0% in group 3 (P < .001), whereas the majority of HBVr in groups 2 and 3 occurred 12 weeks after cessation of entecavir (cumulative incidence, 93.8% in group 2 and 94.7% in group 3). Three patients (5.4%; 1 in each group) showed CR at week 48 and did not receive entecavir treatment. CONCLUSIONS: Twelve weeks of entecavir is suggested to be co-administered with DAA for HCV/HBV dually infected patients. CLINICALTRIALS: gov no: NCT04405011.

Autophagy Drives Galectin-1 Secretion From Tumor-Associated Macrophages Facilitating Hepatocellular Carcinoma Progression.

Galectin-1 (Gal-1) is a secretory lectin with pro-tumor activities and is associated strongly with hepatocellular carcinoma (HCC) development. Although Gal-1 is a well-known soluble pro-tumor factor in the tumor microenvironment (TME), the secretion mode of Gal-1 is not clearly defined. On the other hand, in addition to cancer cells, Gal-1 is widely expressed in tumor stromal cells, including tumor-associated macrophages (TAMs). TAMs are a significant component of stromal cells in TME; however, their contributions in producing Gal-1 to TME are still not explored. Here we reveal that TAMs can actively secrete Gal-1 in response to stimuli of HCC cells. Gal-1 produced by TAMs leads to an increase of the systemic level of Gal-1 and HCC tumor growth in mice. Mechanistically, TLR2-dependent secretory autophagy is found to be responsible for Gal-1 secretion from TAMs. Gal-1 acts as a cargo of autophagosomes to fuse with multivesicular bodies via Rab11 and VAMP7-mediated vesicle trafficking before being secreted. This autophagy-regulated Gal-1 secretion in TAMs correlates to poor overall survival and progression-free survival rates of HCC patients. Our findings uncover the secretion mode of Gal-1 via secretory autophagy and highlight the pathological role of TAM-produced Gal-1 in HCC progression.

Long-term outcome of liver complications in patients with chronic HBV/HCV co-infection after antiviral therapy: a real-world nationwide study on Taiwanese Chronic Hepatitis C Cohort (T-COACH).

BACKGROUND AND AIM: The long-term outcome of hepatitis B virus (HBV) infection among patients dually infected with HBV and hepatitis C virus (HCV) remains unclear. We aimed to investigate the long-term liver outcomes of HBV/HCV-coinfected patients after antiviral therapy. METHODS: A total of 11,359 chronically HCV-infected patients with interferon-based therapy were registered in a nationwide Taiwanese Chronic Hepatitis C Cohort. A propensity score matched (PSM) cohort of HCV mono-infected (n = 7020) and HBV/HCV (n = 702) co-infected patients by age, sex, and fibrosis was recruited for outcome analysis. The primary outcome was liver-related complications, including hepatocellular carcinoma (HCC) and liver decompensation during a mean follow-up period of 4.44 years. RESULTS: Among HBV/HCV co-infected patients, patients without HCV-SVR had a significantly higher 10-year cumulative incidence of major liver-related complications than those with HCV-SVR. However, among patients with HCV-SVR in the PSM cohort, the risk of major liver-related complications, both HCC and liver decompensation, did not differ between HBV/HCV co-infected and HCV mono-infected patients. Similar results were observed among those without HCV-SVR. A substantial lower risk of major liver-related complications was found in HBV/HCV co-infected patients with HCV SVR and subsequent anti-HBV nucleot(s)ide analogues treatment. Overall, factors associated with major liver-related complications included age ≥ 65 year-old, BMI ≥ 27 kg/m2, FIB-4 ≥ 3.25, eGFR < 60 ml/min/1.73 m2, and non-HCV SVR, but not HBV co-infection. CONCLUSION: Interferon-based therapy reduced the long-term risk of major liver-related complications among HBV/HCV co-infected patients, as among HCV mono-infected patients. Nevertheless, post-HCV-SVR surveillance for major liver-related complications is mandatory among those high-risk groups.

Clinical Implications of Serum Hepatitis B Virus Pregenomic RNA Kinetics in Chronic Hepatitis B Patients Receiving Antiviral Treatment and Those Achieving HBsAg Loss.

Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is correlated with covalently closed circular DNA. We aimed to investigate the utility of serum HBV pgRNA in chronic hepatitis B patients receiving nucleos(t)ide analogue treatment and those achieving HBsAg loss. One hundred and eighty-five patients were enrolled for studying long-term HBV pgRNA kinetics during treatment. Twenty patients achieving HBsAg loss after treatment were enrolled for examining HBV pgRNA kinetics around HBsAg loss. HBV pgRNA significantly decreased in the high baseline HBV pgRNA (≥6 log copies/mL) group but significantly increased in the low baseline HBV pgRNA (<4 log copies/mL) group after 3-month entecavir treatment. Among the 20 patients achieving HBsAg loss, 13 (65%) patients had serum HBV pgRNA higher than the limit of detection (LOD, 1466 copies/mL) when they achieved HBsAg loss. Finally, all 20 patients had HBV pgRNA going below the LOD within 3 years after achieving HBsAg loss. In conclusion, baseline serum HBV pgRNA alone is insufficient for predicting the trajectory of HBV pgRNA. Most patients still had HBV pgRNA higher than the LOD when they achieved HBsAg loss. Further studies on HBV pgRNA kinetics around HBsAg loss would provide an enhanced basis for further applications of HBV pgRNA.

Hepatitis C virus eradication decreases the risks of liver cirrhosis and cirrhosis-related complications (Taiwanese chronic hepatitis C cohort).

BACKGROUND AND AIM: It is currently unknown how hepatitis C virus (HCV) eradication with pegylated interferon and ribavirin (PR) therapy affects the incidence of new-onset liver cirrhosis (LC) in patients without cirrhosis and the incidence of decompensated liver disease (DLD) or hepatocellular carcinoma (HCC) in patients with cirrhosis. METHODS: Taiwanese chronic hepatitis C cohort (T-COACH) is a nationwide HCV registry cohort from 23 hospitals in Taiwan recruited between 2003 and 2015. This study enrolled 10 693 patients with chronic hepatitis C (CHC), linked to the Taiwan National Health Insurance Research Database, receiving PR therapy for at least 4 weeks for new-onset LC and liver-related complications (DLD or HCC). RESULTS: Of the 10 693 patients, 1372 (12.8%) patients had LC, and the mean age was 54.0 ± 11.4 years. The mean follow-up duration was 4.38 ± 2.79 years, with overall 46 798 person-years. The 10-year cumulative incidence rates of new-onset LC were 5.0% (95% confidence interval [CI]: 3.2-7.7) in patients without cirrhosis with a sustained virologic response (SVR) and 21.9% (95% CI: 13.4-32.4) in those without SVR (hazard ratio [HR]: 0.22, P < 0.001). The 10-year cumulative incidence rates of liver-related complications were 21.4% (95% CI: 11.1-37.2) in patients with cirrhosis with SVR and 47.0% (95% CI: 11.1-86.0) in those without SVR after adjustment for age, sex, and competing mortality (HR: 0.52, P < 0.001). CONCLUSIONS: Hepatitis C virus eradication with PR therapy decreased the incidence of new-onset LC in noncirrhotic patients and the incidence of liver-related complications in cirrhotic patients with CHC.

Long-term risk of end-stage renal diseases with maintenance dialysis among chronic hepatitis C patients after antiviral therapy in Taiwan.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection is associated with impaired renal function. The aim of this study is to explore the risk of and factors associated with end-stage renal diseases (ESRD) under maintenance dialysis among HCV patients after anti-HCV therapy. METHODS: A total of 12 696 HCV-infected patients with interferon-based therapy, including 9679 (76.2%) achieving sustained virological response (SVR), were enrolled from 23 hospitals in Taiwan. RESULTS: During a mean follow-up period of 5.3 years (67 554 person-years), the annual incidence of 4.1/10 000 person-years, 4.0/10 000 and 4.7/10 000 person-years among SVR patients and non-SVR patients, respectively. History of diabetes and baseline estimated glomerular filtration rate < 60 mL/min/m2 , instead of SVR, were the significant risk factors for developing ESRD with maintenance dialysis after anti-HCV therapy (adjusted hazard ratio 7.75 and 9.78). CONCLUSION: Diabetes and baseline impaired renal function were strongly associated with progression to ESRD with maintenance dialysis among chronic HCV-infected patients after antiviral therapy.

Real-world outcome of immune checkpoint inhibitors for advanced hepatocellular carcinoma with macrovascular tumor thrombosis.

Programmed cell death protein-1 (PD-1) inhibitors have shown promising results for treating advanced hepatocellular carcinoma (HCC). However, the clinical utility of such inhibitors in HCC patients with vascular tumor thrombosis remains unclear. This study investigated PD-1 inhibitor efficacy in advanced HCC with macrovascular invasion in a clinical setting. Among the 110 patients with unresectable HCC treated with PD-1 inhibitors, 34 patients with vascular metastases in the portal vein and inferior vena cava were retrospectively compared with 34 patients without tumor thrombi. The vascular response and its effect on survival were assessed. Predictors of survival were identified using multivariate analysis. Among patients achieving objective response, those with and without thrombi exhibited similar response to immunotherapy and comparable survival. Among the 34 patients with tumor thrombi, including 13 receiving PD-1 inhibitors alone and 21 receiving it in combination with tyrosine kinase inhibitors, the median overall survival was 8.9 months (95% confidence interval 3.2-12.6). The objective response rate of vascular metastasis was 52.9%, and vascular responders had a significantly longer survival than did non-responders (11.1 vs 3.9 months). Failure to obtain a vascular response correlated significantly with increased post-treatment Child-Pugh score or class. Multivariate analysis showed that vascular response was a significant positive factor for longer overall survival. Treatment-related grade 3/4 adverse events occurred in 3 (8.8%) of the patients with tumor thrombi. Immunotherapy with PD-1 inhibitors may be a feasible treatment option for HCC with tumor thrombi owing to the high response rate of tumor thrombi and favorable survival outcomes.

Safety and effectiveness of new embolization microspheres SCBRM for intermediate-stage hepatocellular carcinoma: A feasibility study.

Transarterial chemoembolization (TACE) is, currently, the recommended treatment for hepatocellular carcinoma (HCC). However, long-term chemoembolization triggers the inflammatory response and may lead to postembolization syndrome (PES). Although several types of degradable microspheres have been developed to reduce drug toxicity and PES incidence, the clinical outcomes remain unsatisfactory. Previously, we have developed a new type of spherical, calibrated, biodegradable, radiopaque microspheres (SCBRM) and demonstrated their safety and efficacy in a pig model. Thus, the goal of this feasibility study was to determine the clinical safety and efficacy of the new SCBRM in intermediate-stage HCC patients. In this study, 12 intermediate-stage HCC patients underwent TACE using SCBRM with a calibrated size of 100-250 µm. The disease control rates at 1 month and 3 months after TACE-SCBRM treatment were 100% and 75.0%, respectively. The objective response rates at 1 month and 3 months after treatment were 66.7% and 58.3%, respectively. Very few adverse events were observed with one patient developing nausea. One day after the treatment, alanine aminotransferase, alanine aminotransferase, and total bilirubin levels were slightly elevated in the patients, but all returned to baseline on day 7. The median and mean overall survival times were 33 months (interquartile range, 12.8-42.0) and 29.2 ± 14.3 months, respectively. The 1-year and 2-year survival rates were 91.7% and 58.3%, respectively. In conclusion, TACE with the new SCBRM microspheres is clinically safe and effective, and it represents a promising approach in the management of intermediate-stage HCC.

Effectiveness and safety of ledipasvir/sofosbuvir for genotype 2 chronic hepatitis C infection: Real-world experience from Taiwan.

BACKGROUND/PURPOSE: Genotype 2 (GT2) hepatitis C virus infection is the second common genotype in Taiwan. Real-world experience of ledipasvir/sofosbuvir (LDV/SOF) for GT2 infection is limited. The aim of this study is to evaluate the effectiveness and safety of LDV/SOF in patients with GT2 chronic hepatitis C (CHC) infection. METHODS: CHC patients with GT2 infection receiving 12 weeks LDV/SOF from three hospitals were enrolled. HCV RNA was checked at baseline, end-of-treatment and 12 weeks after completing treatment. Demographic data, adverse events, renal function and metabolic profiles were recorded. RESULTS: Among 392 enrolled patients, 33 patients (8.4%) were cirrhotic. Sustained virological response (SVR) rate was 96.7% (379/392) by intention-to-treat analysis and 97.2% (379/390) by per-protocol analysis. The SVR rate was lower in cirrhotic patients than in non-cirrhotic patients (90.6% vs 97.8%, p = 0.053). Two cirrhotic patients who took LDV/SOF plus ribavirin both achieved SVR. Neither drug-related severe adverse events nor discontinuation due to drug-related adverse event were reported. The estimated glomerular filtration rate (eGFR) remained stable in patients with chronic kidney disease 3a/3b. CONCLUSION: Twelve weeks of LDV/SOF treatment provided an excellent and safe regimen for GT2 CHC infection, particularly in non-cirrhotic patients.

Persistent augmentation of central arterial stiffness following viral clearance by direct-acting antivirals in chronic hepatitis C.

Chronic hepatitis C virus (HCV) infection is associated with risk of cardiovascular diseases. Although direct-acting antivirals (DAA) result in rapid eradication of HCV, their long-term impact on arterial stiffness remains unclear. This study aimed to evaluate changes in parameters of central arterial stiffness from pretreatment, through sustained virological response, to one year after viral clearance. Patients with chronic HCV receiving DAA treatment were enrolled prospectively. Medical history and comorbidities of all patients were collected. Lipid profiles, liver stiffness by transient elastography and central blood pressures using pulse wave analysis of the brachial artery by cuff sphygmomanometry were measured before treatment, at viral clearance and at one year following viral clearance. Augmentation index (AIx), a parameter of aortic stiffness, was calculated as the ratio of augmentation pressure to central pulse pressure. After DAA treatment, all included patients with chronic HCV (n = 102) had achieved viral clearance. Cholesterol, low-density lipoprotein (LDL) and triglyceride/high-density lipoprotein (TG/HDL) increased significantly at viral clearance and persisted at one year (all P < .001). AIx was also elevated significantly at viral clearance and persisted one year later (P < .001). Changes in AIx remained significant only in patients with increased values from baseline in either LDL (P < .01) or TG/HDL (P < .001). Central arterial stiffness and lipid profiles in patients with chronic HCV worsen immediately after viral eradication by DAA treatment and persist at one year. Worsening of lipid profiles after DAA treatment contributes to central arterial stiffness in this patient population and persists long term.