Hsiu J. Ho

Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients

Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population‐based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8‐year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3‐2.0%), 9.3% (95% CI, 5.9‐12.7%), and 3.3% (95% CI, 2.3‐4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1‐5.0%), 5.3% (95% CI, 3.0‐7.5%), and 6.1% (95% CI, 4.8‐7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1‐6.1%), 6.6% (95% CI, 3.7‐9.5%), and 7.4% (95% CI, 5.9‐9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate‐adjusted hazard ratios of 0.16 (95% CI, 0.07‐0.33%) for ESRD, 0.53 (95% CI, 0.30‐0.93) for ischemic stroke, and 0.64 (95% CI, 0.39‐1.06) for ACS. Conclusion: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. (Hepatology 2014;59:1293‐1302)

Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection

Objective To elucidate the association between antiviral therapy and extrahepatic outcomes in individuals infected with HCV. Methods This nationwide cohort study screened 293 480 Taiwanese residents with HCV infection and excluded those with substantial comorbidity. A total of 12 384 eligible patients who had received pegylated interferon plus ribavirin between 1 October 2003 and 31 December 2010 were enrolled in the treated cohort; they were matched 1 : 2 with 24 768 untreated controls in the propensity score and post-diagnosis treatment-free period. The incidences of end-stage renal disease (ESRD), acute coronary syndrome (ACS), ischaemic stroke and catastrophic autoimmune diseases were calculated after adjustment for competing mortality. Results The treated and untreated cohorts were followed up for a mean (±SD) duration of 3.3 (±2.5) and 3.2 (±2.4) years, respectively, until 31 December 2011. The calculated 8-year cumulative incidences of ESRD, ACS, ischaemic stroke and autoimmune catastrophes between treated and untreated patients were 0.15% vs 1.32% (p<0.001), 2.21% vs 2.96% (p=0.027), 1.31% vs 1.76% (p=0.001) and 0.57% vs 0.49% (p=0.816), respectively. Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of ESRD (HR 0.15; 95% CI 0.07 to 0.31; p<0.001), ACS (HR 0.77; 95% CI 0.62 to 0.97; p=0.026) and ischaemic stroke (HR 0.62; 95% CI 0.46 to 0.83; p=0.001), but unrelated to autoimmune catastrophes. These favourable associations were invalid in incompletely treated patients with duration <16 weeks. Conclusions Antiviral treatment for HCV is associated with improved renal and circulatory outcomes, but unrelated to catastrophic autoimmune diseases.

Postoperative peg‐interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus‐related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) frequently recurs after surgical resection. This population‐based research aimed to investigate the association between postoperative antiviral treatment and risk of recurrent HCC in patients with hepatitis C virus (HCV) infection. By analyzing the Taiwan National Health Insurance Research Database, we initially screened a total of 100,938 patients diagnosed with HCC for the first time between October 2003 and December 2010. Among 2,237 antiviral‐naïve HCV‐infected patients with curatively resected HCC, there were 213 patients receiving antiviral treatment with pegylated interferon plus ribavirin for 16 weeks or more after surgery (treated cohort). These treated patients were matched 1:4 with 852 controls who were never treated for HCV infection (untreated cohort) by age, gender, cirrhosis, and the elapsed time between surgery and antiviral therapy. Cumulative incidences of and hazard ratios for recurrent HCC were calculated after adjusting for competing mortality. The recurrence rate of HCC was significantly lower in the treated than untreated cohort, with 52.1% (95% confidence interval [CI], 42.0‐62.2%) and 63.9% (95% CI, 58.9‐68.8%) after 5 years of follow‐up, respectively (P = 0.001). The number needed to treat for one fewer recurrent HCC at 5 years was 8. The association between postoperative antiviral treatment and risk of recurrent HCC was independent of adjustment for multiple covariates, with an adjusted hazard ratio of 0.64 (95% CI, 0.50‐0.83). Stratified analyses revealed that the attenuation in recurrence risk was greater in patients younger than 60 years and those without cirrhosis or diabetes. Conclusion: Postoperative pegylated interferon plus ribavirin is associated with reduced recurrence of HCC in patients with HCV infection. Age, liver cirrhosis, and diabetes mellitus appear to modify this association. (HEPATOLOGY 2013)

Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study

Objective Current guidelines recommend screening for hepatocellular carcinoma (HCC) in high-risk populations. However, the effectiveness of screening in reducing mortality has been challenged. In addition, it is unclear which subgroups benefit most from HCC screening. Design This nationwide cohort study identified a total of 52 823 newly diagnosed HCC patients between 1 January 2002 and 31 December 2007. These HCC patients were classified into the following cohorts according to the time intervals in which they received ultrasonography screening: 0–6 months (6M), 7–12 months (12M), 13–24 months (24M), 25–36 months (36M) and not screened within 3 years (never screened). The chance to receive curative therapy and 5-year cumulative mortalities were calculated after adjusting for lead-time bias. Results Chances to receive curative therapy among the 6M, 12M, 24M, 36M and never screened cohorts were 24.3% (95% CI 23.7% to –24.9%), 26.9% (95% CI 25.7% to 28.2%), 22.9% (95% CI 21.8% to 24.1%), 21.3% (95% CI 19.9% to 22.8%) and 18.3% (95% CI 17.8% to 18.8%), respectively. Compared with the 6M cohort, adjusted HRs of mortality for the 12M, 24M, 36M and never screened cohorts were 1.11 (95% CI 1.07 to 1.15), 1.23 (95% CI 1.19 to 1.28), 1.31 (95% CI 1.26 to 1.37) and 1.47 (95% CI 1.43 to 1.51) (all p Conclusions Shorter ultrasonography screening intervals are associated with reduced overall mortality in HCC patients in a dose-dependent manner.

First-line Helicobacter pylori eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis.

Objective To determine the optimal regimen of different first-line Helicobacter pylori eradication therapies according to the clarithromycin resistance rate. Design Electronic search for articles published between January 2005 and April 2016. Randomised, controlled trials that reported the effectiveness of first-line eradication therapies in treatment-naïve adults were included. Two independent reviewers performed articles screening and data extraction. Network and traditional meta-analyses were conducted using the random effect model. Subgroup analyses were performed to determine the ranking of regimens in countries with high (>15%) and low (<15%) clarithromycin resistance. Data including adverse events and therapeutic cure rate were also extracted and analysed. Results 117 trials (totally 32 852 patients) for 17 H. pylori eradication regimens were eligible for inclusion. Compared with 7-day clarithromycin-based triple therapy, sequential therapy (ST) for 14 days had the highest effectiveness (OR=3.74, 95% CrI 2.37 to 5.96). ST-14 (OR=6.53, 95% CrI 3.23 to 13.63) and hybrid therapy (HY) for 10 days or more (OR=2.85, 95% CrI 1.58 to 5.37) represented the most effective regimen in areas with high and low clarithromycin resistance, respectively. The effectiveness of standard triple therapy was below therapeutic eradication rate in most of the countries. Longer duration was associated with higher eradication rate, but with a higher risk of events that lead to discontinuation. Conclusions ST and HY appeared to be the most effective therapies in countries with high and low clarithromycin resistance, respectively. The clinical decision for optimal regimen can be supported by referring to the rank ordering of relative efficacies stratified by local eradication rates, antibiotic resistance and safety profile. Trial registration number CRD42015025445.

The Incidence of Gastric Adenocarcinoma Among Patients With Gastric Intestinal Metaplasia: A Long-term Cohort Study.

Background and Aims: Gastric intestinal metaplasia (IM) has been known as a premalignant condition, but estimates of its cancer risk vary widely. We aimed to analyze cancer risk of gastric IM by a long-term cohort study. Methods: We conducted a hospital-based study that included all patients with gastric IM between 1992 and 2010, and the development of gastric adenocarcinoma was evaluated until July 2011. Patients developing gastric cancer ⩽180 days after the index diagnosis of IM were excluded. The incidence rate, the cumulative incidence, and the standardized incidence ratio (SIR) of gastric cancer were determined, and hazard ratios (HRs) of risk factors were calculated. Results: We identified 7059 patients with a median follow-up duration of 5.1 years, and 81 patients developed gastric adenocarcinoma during the study period. The 5-, 10-, and 15-year cumulative incidences of gastric cancer were 0.9% [95% confidence interval (CI), 0.6-1.1), 2.0% (95% CI, 1.5-2.6), and 3.0% (95% CI, 2.0-4.0), respectively. On multivariate analysis, older age (eg, 75 y and above; HR=7.4; 95% CI, 2.8-19.6), low-grade dysplasia (HR=4.0; 95% CI, 2.1-7.9), and high-grade dysplasia (HR=18.8; 95% CI, 9.0-39.5) were independent risk factors. As compared with the risk in the general population, the SIR of gastric cancer among patients with gastric IM was 2.5 (95% CI, 2.0-3.1). However, the SIR was only 2.0 (95% CI, 1.5-2.6) in the nondysplasia subgroup, but was up to 35.2 (95% CI, 15.2-69.4) in the high-grade dysplasia subgroup. Conclusions: Gastric IM is an important risk factor for gastric cancer, but surveillance should be arranged only for those at an especially high risk.

Simvastatin-induced cell cycle arrest through inhibition of STAT3/SKP2 axis and activation of AMPK to promote p27 and p21 accumulation in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and is one of the leading causes of cancer-related death worldwide. Simvastatin, an HMG-CoA reductase inhibitor, which decreases cholesterol synthesis by inhibiting mevalonate pathways and is widely used to treat cardiovascular diseases. Simvastatin exhibits anticancer effects against several malignancies. However, the molecular mechanisms underlying the anticancer effects of simvastatin on HCC are still not well understood. In this study, we demonstrated simvastatin-induced G0/G1 arrest by inducing p21 and p27 accumulation in HepG2 and Hep3B cells. Simvastatin also promoted AMP-activated protein kinase (AMPK) activation, which induced p21 upregulation by increasing its transcription. Consistent with this finding, we found genetic silencing of AMPK reduced p21 expression; however, AMPK silencing had no effect on p27 expression in HCC cells. Simvastatin decreased Skp2 expression at the transcriptional level, which resulted in p27 accumulation by preventing proteasomal degradation, an effect mediated by signal transducer and activator of transcription 3 (STAT3) inhibition. Constitutive STAT3 activation maintained high-level Skp2 expression and lower level p27 expression and significantly prevented G0/G1 arrest in simvastatin-treated HCC cells. Mevalonate decreased simvastatin-induced AMPK activation and rescued phospho-STAT3 and Skp2 expression in HCC cells, which resulted in the prevention of G0/G1 arrest through inhibition of p21 and p27 accumulation. Moreover, simvastatin significantly decreased tumor growth in HepG2 xenograft mice. Consistently, we found that simvastatin also increased p21 and p27 expression in tumor sections by reducing Skp2 expression and inducing AMPK activation and STAT3 suppression in the same tumor tissues. Taken together, these findings are demonstrative of the existence of a novel pathway in which simvastatin induces G0/G1 arrest by upregulating p21 and p27 by activating AMPK and inhibiting the STAT3–Skp2 axis, respectively. The results identify novel targets that explain the beneficial anticancer effects of simvastatin treatment on HCC in vitro and in vivo.

Evaluation of the Effect of Cumulative Operator Experience on Hepatocellular Carcinoma Recurrence after Primary Treatment with Radiofrequency Ablation

PURPOSE To investigate the association between cumulative operator volume and the risk of hepatocellular carcinoma (HCC) recurrence after potentially curative radiofrequency ablation (RFA). MATERIALS AND METHODS This study was approved by the Research Ethics Committee. By using the Taiwan National Health Insurance Research Database, 52 096 patients with HCC were identified between July 1, 2004, and December 31, 2011. In total, 2827 patients were selected who underwent potentially curative RFA for newly diagnosed HCC. These patients were grouped into quintiles according to the cumulative operator volumes. Patients in the lowest or the highest quintiles were 1:1 matched according to their propensity scores. Finally, two separate groups, each containing 406 patients, were recruited in the high- and low-volume groups (cumulative operator volume of ≥79 cases and ≤10 cases, respectively). Cumulative incidences of and hazard ratios for HCC recurrence were analyzed after adjusting for competing mortality. RESULTS The HCC recurrence rate of the high-volume group was significantly lower than that of the low-volume group (high-volume group 5-year recurrence rate of 65.8%, 95% confidence interval [CI]: 59.5%, 72.1%; low-volume group 5-year recurrence rate of 71.4%, 95% CI: 66.2%, 76.5%; P < .05). In modified Cox regression analysis, the highest cumulative operator volume was independently associated with a decreased risk of HCC recurrence (hazard ratio, 0.80; 95% CI: 0.67, 0.97; P < .05). Multivariable stratified analyses verified the association between the highest cumulative operator volume and decreased HCC recurrence in almost all subgroups. CONCLUSION The risk of HCC recurrence could be significantly decreased by experienced RFA operators. Further studies based on cumulative operator volume may be helpful in improving the quality of RFA for HCC.

Gastric microbiota and predicted gene functions are altered after subtotal gastrectomy in patients with gastric cancer

Subtotal gastrectomy (i.e., partial removal of the stomach), a surgical treatment for early-stage distal gastric cancer, is usually accompanied by highly selective vagotomy and Billroth II reconstruction, leading to dramatic changes in the gastric environment. Based on accumulating evidence of a strong link between human gut microbiota and host health, a 2-year follow-up study was conducted to characterize the effects of subtotal gastrectomy. Gastric microbiota and predicted gene functions inferred from 16S rRNA gene sequencing were analyzed before and after surgery. The results demonstrated that gastric microbiota is significantly more diverse after surgery. Ralstonia and Helicobacter were the top two genera of discriminant abundance in the cancerous stomach before surgery, while Streptococcus and Prevotella were the two most abundant genera after tumor excision. Furthermore, N-nitrosation genes were prevalent before surgery, whereas bile salt hydrolase, NO and N2O reductase were prevalent afterward. To our knowledge, this is the first report to document changes in gastric microbiota before and after surgical treatment of stomach cancer.

Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) during antiviral therapy in patients with chronic hepatitis B (CHB) is inadequately predicted by the scores built from untreated patients. We aimed at developing and validating a risk score to predict HCC in patients with CHB on entecavir or tenofovir treatment. METHODS This study analysed population-wide data from the healthcare databases in Taiwan and Hong Kong to identify patients with CHB continuously receiving entecavir or tenofovir. The development cohort included 23,851 patients from Taiwan; 596 (2.50%) of them developed HCC with a three-year cumulative incidence of 3.56% (95% CI 3.26-3.86%). The multivariable Cox proportional hazards model found that cirrhosis, age (cirrhosis and age interacted with each other), male sex, and diabetes mellitus were the risk determinants. These variables were weighted to develop the cirrhosis, age, male sex, and diabetes mellitus (CAMD) score ranging from 0 to 19 points. The score was externally validated in 19,321 patients from Hong Kong. RESULTS The c indices for HCC in the development cohort were 0.83 (95% CI 0.81-0.84), 0.82 (95% CI 0.81-0.84), and 0.82 (95% CI 0.80-0.83) at the first, second, and third years of therapy, respectively. In the validation cohort, the c indices were 0.74 (95% CI 0.71-0.77), 0.75 (95% CI 0.73-0.78), and 0.75 (95% CI 0.72-0.77) during the first three years, and 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.77) in the extrapolated fourth and fifth years, respectively. The predicted and observed probabilities of HCC were calibrated in both cohorts. A score <8 and >13 points identified patients at distinctly low and high risks. CONCLUSIONS The easily calculable CAMD score can predict HCC and may inform surveillance policy in patients with CHB during oral antiviral therapy. LAY SUMMARY This study analyses population-wide data from the healthcare systems in Taiwan and Hong Kong to develop and validate a risk score that predicts hepatocellular carcinoma during oral antiviral therapy in patients with chronic hepatitis B. The easily calculable CAMD score requires only simple information (i.e. cirrhosis, age, male sex, and diabetes mellitus) at the baseline of treatment initiation. With a scoring range from 0 to 19 points, the CAMD score discriminates the risk of hepatocellular carcinoma with a concordance rate of around 75-80% during the first three years on therapy. The risk prediction can be extrapolated to five years on treatment with similar accuracy. Patients with a score <8 and >13 points were exposed to distinctly lower and higher risks, respectively.