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Background/Purpose Pegylated interferon (PegIFN) plus ribavirin (RBV) combination therapy has been the standard of care since 2002. Although a better viral response has been achieved among chronic hepatitis C (CHC) patients in Taiwan, approximately 25% of hepatitis C virus (HCV) genotype 1 (G1) patients and 15% of G2 patients failed to achieve a sustained virological response (SVR) at the first therapy. The actual cost-effectiveness of the retreatment remains elusive. The present study conducted a real-world cost-effectiveness analysis of a large cohort among different pre-specified subgroups of treatment-experienced CHC patients. Methods A total of 117 patients with CHC who failed to achieve SVR at the first IFN-based therapy and received a second IFN-based therapy were enrolled. The inpatient and outpatient costs were acquired from National Health Insurance Research Database of Taiwan. The related medical care costs per treatment and per SVR were calculated. Results We demonstrated that the average cost per SVR achieved was $13,722 in treatment-experienced CHC patients. Especially, patients with HCV G1 infection, baseline viral loads > 400,000 IU/mL, advanced hepatic fibrosis, not achieving a rapid viral response at week 4 or complete early viral response at week 12, had poorer cost-effectiveness for PegIFN/RBV retherapy, ranging from around $15,520 to as high as $72,546 per SVR achieved. Conclusion In the current study, we explored the real-world cost-effectiveness data of PegIFN/RBV for different subgroups of treatment-experienced HCV patients. These findings provide information for policy-makers for making decisions on treatment strategies of costly direct-acting antiviral agents for retreating CHC patients.

Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe β-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as β-thalassemia and SCD.

The prevalence and characteristics of patients with hepatitis C virus mixed genotype 1 and 2 infection (HCV-1/2) remains unclear. For each HCV-1/2 patient with histological data available, two age- and sex-matched HCV-1 and HCV-2 infected patients were selected for comparison, respectively. Of the 2776 patients, 261 (9.4%) patients were identified as having mixed HCV-1/2 infection. The histological severity did not differ among HCV-1/2 patients and controls. The proportion of patients with the interleukin-28B (IL-28B) rs8099917 TT genotype did not differ between patients with mixed-1/2 and HCV-1 infection (82.6% vs. 86.5%, p = 0.38). However, HCV-2 infected patients had a significantly higher proportion of the rs8099917 TT genotype compared to patients with mixed HCV-1/2 infections (91.6% vs. 82.6%, p = 0.03). The HCV RNA levels were similar in patients with HCV-1/2 and HCV-1 infections (5.5 ± 0.8 log IU/mL vs. 5.5 ± 0.9 log IU/L, p = 0.73), which were both significantly higher than that of HCV-2 infection (5.1 ± 0.9 log IU/mL, both p

Background & Aims Genetic variants of patatin-like phospholipase domain-containing 3 ( PNPLA3 ) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. Methods The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. Results Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p= 0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p= 0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008–1.037, p= 0.002), diabetes (OR: 1.81, CI: 1.236–2.653, p= 0.002), α-fetoprotein (OR: 1.006, CI: 1.001–1.01, p= 0.01), platelet counts (OR: 1.009, CI: 1.006–1.012, p 0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006–1.785, p= 0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356–15.106, p= 0.014) or the dominant model (OR: 2.20, CI: 1.026–4.734, p= 0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889–26.719, p 0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048–2.286, p= 0.03). Conclusions The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic–environmental interaction contributed to the high risk of advanced liver disease in CHC patients.

Background & Aims: Hepatitis C virus (HCV)-infected patients with cirrhosis remain at risk of hepatocellular carcinoma (HCC) even after achieving sustained virological response (SVR). The aim of the study was to explore the incidence and risk for HCC among non-cirrhotic patients with an SVR. Methods: A total of 642 patients with an SVR after peginterferon/ ribavirin therapy were enrolled with a median follow-up period of 53.0 months (range: 6–133 months). Results: Thirty-three of the 642 (5.1%) patients developed HCC over 2324.8 person-years of follow-up. Cox regression analysis revealed that the strongest predictive factor of HCC occurrence was liver cirrhosis (HR 4.98, 95% CI 2.32–10.71, p

A substantial proportion of hepatitis C virus genotype 1 (HCV-1) patients achieved a sustained virological response (SVR, HCV RNA seronegative throughout 24 weeks of post-treatment follow-up) after 24 weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen.Interleukin-28B rs8099917 genotype was determined in 226 HCV-1 patients with 24 weeks peginterferon/ribavirin.Compared to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, HCV RNA seronegative at treatment week 4, 54.0% vs. 17.9%, p0.001) and SVR (64.7% vs. 25.6%, p0.001) rates, and lower relapse rate (28.0% vs. 54.5%, p=0.01). Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/ 95% confidence intervals [OR/CI]: 6.24/2.34-16.63), followed by lower viral loads (OR/CI: 5.29/2.81-9.93) and age (OR/CI:0.94/0.91-9.97). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 22.23/9.22-53.58), followed by the carriage of rs8099917 TT genotype (OR/CI: 3.38/1.18-9.65), lower viral loads (OR/CI: 2.23/1.00-4.93) and ribavirin exposure dose (OR/CI: 1.17/1.06-1.30). The determinant power of rs8099917 genotype on SVR was mainly restricted to non-RVR patients, particularly those with higher baseline viral loads. Combination of the two pretreatment predictors, interleukin-28B genotype and baseline viral loads, could predict treatment efficacy with a positive predictive value of 80% and a negative predictive value of 91%.Interleukin-28B genotype could help identifying patients who are or are not candidates for an abbreviated regimen before treatment.

Vascular endothelial growth factor (VEGF), angiopoietin-2, and endostatin have been reported to be related with angiogenesis of hepatocellular carcinoma (HCC). The potential feasibility of serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with HCC treated by transcatheter arterial chemoembolization (TACE) was investigated. VEGF-A, angiopoietin-2, and endostatin serum level were determined by enzyme-linked immunosorbent assay 1 day before and 7 days after TACE in 40 patients. Then they were followed up for 3 months. The results showed that TACE could cause significant increase of VEGF-A (p 0.1). Twenty-five patients with rapid growth of HCC within 3 months after TACE had higher proportion of American Joint Committee on Cancer HCC staging >II and higher increase of VEGF-A after TACE than 15 patients without rapid growth (all p 16.7 pg/mL 7 days after TACE selected by receiver operating characteristic curve analysis (p

Background & Aims Evidence on the efficacy of antiviral treatment in chronic hepatitis C (CHC) patients with hepatocellular carcinoma (HCC) after curative treatment is scarce. We aimed to evaluate the efficacy and safety of pegylated interferon-alpha plus ribavirin (pegIFN/RBV) combination therapy in these patients, compared to cirrhotic patients. Methods This prospective, multicenter, case–control study recruited 82 consecutive CHC patients with HCC after curative management and 87 sex/age-matched cirrhotic patients. All patients received pegIFN-alpha-2a and weight-based RBV according to current treatment recommendations. The primary outcome measurement was sustained virological response (SVR, seronegative of hepatitis C virus RNA throughout the 6-month post-treatment follow-up period). Results The SVR rate was significantly lower in the HCC group compared to the cirrhosis group (48.8% vs 64.4%, p =0.04). However, the significantly lower rate of SVR in the HCC group was observed among genotype-1 patients (33.3% vs 60.7%, p =0.005) but not among genotype-2/3 patients (70.6% vs 71.0%, p =0.88). In patients who achieved 80/80/80 adherence, there was no significant difference of SVR rate between groups (50.7% vs 64.2%, p =0.12) Multivariate logistic regression analysis demonstrated that rapid virological response (viral clearance during the first 4weeks of treatment, odds ratio=22.1, p p =0.05) were predictive factors associated with SVR, whilst previous occurrence of HCC was not associated with SVR (Odds ratio=0.4, p =0.09). The incidence of severe adverse events did not differ between the two groups. Conclusions The study proved the feasibility of pegIFN/RBV therapy with current treatment guidelines in CHC patients after successful eradication of HCC, with careful monitoring.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causes of liver disease in Taiwan and have a great impact on the health of this country. This study investigated the seroprevalence of HBV and HCV in southern Taiwan. Screening programs were performed from September 1999 to August 2005 for community-based surveillance of liver disease. A total of 28,797 adults from southern Taiwan, including Kaohsiung City (n = 14,036), Kaohsiung County (n = 7,713), and Pingtung County (n = 7,048) were participated. The mean age was 50.3 ± 14.6 years (range, 20-97 years), with 41.0% were men. Hepatitis B surface antigen (HBsAg), antibody to HCV (anti-HCV), and liver function tests were performed. Among the 28,797 adults, the prevalence of HBsAg(+) was 15.1% and that for anti-HCV(+) was 8.6%. The seroprevalence of HBsAg in Kaohsiung County was 18.2%, which was higher than in Kaohsiung City (14.7%, p < 0.001) or Pingtung County (12.5%, p < 0.001). The seroprevalence of anti-HCV in Kaohsiung County was 17.2%, which was higher than in the other regions (Kaohsiung City = 5.8%, p < 0.001; Pingtung County = 4.6%, p < 0.001). The prevalence of dual HBsAg and anti-HCV was 1.1% (323 patients). Tzukuan Township in Kaohsiung County was endemic for HBsAg (19.1%, 1,026/5,375 patients), anti-HCV (22.4%, 1,203/5,375 patients), and dual HBsAg/anti-HCV (3.6%, 191/5,375 patients). Subjects with anti-HCV(+) were older and had higher alanine transaminase levels than their HBsAg(+) counterparts (p < 0.001 and p < 0.001, respectively). The current study shows the epidemiological characteristics of HBV and HCV infections among adults in southern Taiwan. Viral hepatitis infections remain widely endemic in this region.

Hepatitis C virus (HCV) infection has been shown to be associated with a low platelet count. This study aimed to elucidate the association between virologic status and platelet count in individuals with HCV infection.A large-scale survey, enrolling 11,239 residents, was conducted in the Kaohsiung area of Taiwan. Serum HCV RNA and non-invasive markers of fibrosis (FibroTest) were tested for antibody to HCV (anti-HCV)-positive subjects. The platelet counts of age- and sex-matched, biopsy-proven, hospital-based patients and community-based patients with minimal fibrosis were compared.Anti-HCV was positive in 703 (6.2%) subjects and was significantly associated with older age, female sex, abnormal alanine aminotransferase (ALT) value and low platelet count (150,000/microl). The independent factors significantly associated with low platelet count were abnormal ALT value (odds ratio [OR]: 3.70, 95% confidence intervals [CI]: 2.18-6.28) and positive HCV RNA (OR: 2.00, 95% CI: 1.01-3.97). After adjustment for the fibrosis, HCV RNA remained significantly associated with platelet counts.Our results evaluating the association between platelet count and HCV viremia and taking the influences of fibrosis into consideration implicate that platelets may be affected directly by HCV.

The production of transforming growth factor beta 1 (TGF-beta1) has been reported as being significantly associated with the gene polymorphism in the leader sequence at positions +29. The current study aimed to evaluate the associations between the polymorphism and the clinical characteristics of chronic hepatitis C (CHC). A total of 422 (252 men; mean age: 49.7 +/- 11.2 years) Taiwanese CHC patients with liver biopsies were enrolled. The TGF-beta1 gene polymorphism at position +29 (T or C), hepatitis C virus (HCV) RNA genotypes, and serum HCV RNA levels of these patients were determined. Of the 422 patients, the frequency of the T allele was 45.4%. Based on univariate analyses, a significantly lesser proportion of patients with allele T had high viral loads than those who were without allele T (P = 0.026). The lesser HCV RNA levels and HCV genotype 1b infection were significantly associated with the inheritance of the T allele in female patients based on univariate (P = 0.012 and 0.007, respectively) and multivariate regression (odds ratio/95% confidence interval: 0.434/0.219-0.859 and 0.468/0.237-0.927, respectively) analyses. In male patients with or without inheritance of the T allele, the clinical characteristics were similar. In conclusion, the association between TGF-beta1 polymorphism and virologic characteristics of chronic HCV infection implicated a significant role of host genetic factors on the clinical features of CHC. Female patients who carry T allele at position +29 were predisposed to be associated with HCV genotype non-1b infection and lesser HCV viral load, which revealed the gender effect.

Background/Aims To evaluate the association of virologic status with serum cholesterol and triglyceride levels in individuals with hepatitis C virus (HCV) infection. Methods We conducted a large scale community-based study enrolling 11,239 residents in an area endemic for hepatitis B virus (HBV) and HCV infection in southern Taiwan. Overall, 703 (6.3%), 1,536 (13.7%), 84 (0.7%) and 9,084 (80.8%) subjects were sero-positive for anti-HCV antibody (anti-HCV), hepatitis B surface antigen (HBsAg), and both anti-HCV and HBsAg, and negative for anti-HCV and HBsAg, respectively. Results By multivariate logistic analyses, the independent factors significantly associated with elevated serum cholesterol level were older age, female, negative for diabetes, anti-HCV or HBsAg and elevated triglyceride levels. The independent factors significantly associated with elevated serum triglyceride level were male, positive for diabetes, negative for anti-HCV or HBsAg, higher body mass index (BMI) and elevated cholesterol levels. Of 642 anti-HCV-positive subjects that have HCV RNA tested by standardized automated qualitative PCR assay, 478 (74.5%) were positive for HCV RNA. By multivariate logistic analyses, the independent factors associated with elevated serum cholesterol level were female, elevated serum triglyceride levels, negative for diabetes or HCV RNA. The independent factors associated with elevated serum triglyceride levels were elevated serum cholesterol levels, positive for diabetes, higher BMI and negative for HCV RNA. Diabetes, lower cholesterol and triglyceride levels were independent factors associated with positive HCV RNA. Conclusions Based on the result of this large scale community study, HCV viremia appears to be associated with lower serum cholesterol and triglyceride levels which implies that HCV itself might play a significant role on serum lipid profile of patients with chronic HCV infection.

The prevalence and clinical significance of two SEN virus (SENV) strains, SENV-D and SENV-H, was investigated among patients on maintenance hemodialysis in southern Taiwan.Sera from 99 uremic patients were tested for alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), and SENV-D and -H DNA. Sera from 120 healthy blood donors were tested as a control group.Of the 99 patients, 24.2 and 7.1% were positive for anti-HCV and HBsAg, respectively, and the prevalence of SENV-D and/or -H (SENV-D/H), SENV-D and SENV-H DNA was 61.6, 46.5 and 27.3%, which was significantly higher than for donors (23.3, 18.3, and 5.8%, respectively; all P0.0001). Patients with SENV-D DNA had significantly higher mean age among both patients (P=0.019) and donors (P=0.015). Mean serum ALT levels were significantly higher among patients with anti-HCV (P=0.003) and patients with SENV-D and -H concurrent infection (P=0.034). By multivariate analyses, the presence of serum anti-HCV and concurrent SENV-D and -H infection were independent factors associated with increased ALT level.The prevalence of SENV-D/H infection is high among Taiwanese patients on maintenance hemodialysis with SENV-D more prevalent than SENV-H. The ALT level was associated with not only positive anti-HCV but also concomitant viremia of both SENV-D and SENV-H.