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The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10–0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13–0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04–40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.

Background/Aims: Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC.Methods: The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed.Results: GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II–IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C.Conclusions: Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11–19.46, P P = 0.02), age > 50 years old (HR/CI 3.64/2.03–6.54, P P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03–1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04–19.09, P = 0.04) and BMI (HR/CI 1.11/1.03–1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.

BACKGROUND AND AIM The serial serologic changes of hepatitis D virus (HDV) infection among chronic hepatitis B virus (HBV) infected patients who received oral nucleotide/nucleoside analogues are elusive. METHODS Serum anti-HDV and HDV RNA among chronic hepatitis B (CHB) patients were tested at the time of initiating anti-HBV therapy and subsequently during the follow-up period. RESULTS The seropositive rate of anti-HDV and HDV RNA among 2850 CHB patients, was 2.7% and 0.9%, respectively. Factors associated with anti-HDV seropositivity were platelet counts (odds ratio [OR]/95% confidence intervals [CI]: 0.995/0.992-0.999; P = 0.006), HBV DNA levels (OR/CI: 0.81/0.70-0.94; P = 0.005), and hepatitis B e-antigen (HBeAg) seropositivity (OR/CI: 0.22/0.05-0.95; P = 0.04). The only factor associated with HDV RNA positivity among anti-HDV seropositive patients was age (OR/CI: 0.95/0.90-1.00; P = 0.03). The spontaneous clearance rate of serum anti-HDV antibody was 3.0 per 100 person-years with a median follow-up period of 3.5 years (range 2-12 years), whereas the seroclearance rate of HDV RNA was 4.3 per 100 person-years among anti-HDV seropositive patients after a median follow-up period of 6.0 years (range 2-11 years). A baseline anti-HDV titer

Background: The biochemical response is a crucial indicator of prognosis in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs). The impact of hepatitis D virus (HDV) infection on alanine aminotransferase normalization is elusive. Methods: The longitudinal study recruited 1185 CHB patients who received NAs. These patients were tested for anti-HDV antibody and HDV RNA at the initiation of anti-hepatitis B virus (HBV) therapy and annually for patients who were HDV-seropositive. ALT levels were examined at the first and second year of anti-HBV therapy. ALT abnormality was defined as ALT levels above 40 IU/mL in both male and female, and the risk factors associated with ALT abnormality were analysed. Results: Rates of seropositivity for anti-HDV and HDV RNA were 2.0% and 0.8% among 1185 NA-treated CHB patients, respectively. The strongest factor associated with ALT abnormality (>40 IU/mL) after first year treatment with NAs was HDV RNA seropositivity at year 1 (odds ratio [OR]/95% confidence interval [CI]: 31.44/3.49–283.56, P = 0.002), followed by liver cirrhosis (2.18/1.51–3.15, P

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.

// Chung-Feng Huang 1, 2, 3 , Ching-I Huang 1 , Ming-Lun Yeh 1, 2 , Shu-Chi Wang 1 , Kuan-Yu Chen 1 , Yu-Min Ko 1 , Ching-Chih Lin 1 , Yi-Shan Tsai 1 , Pei-Chien Tsai 1 , Zu-Yau Lin 1, 2 , Shinn-Cherng Chen 1, 2 , Chia-Yen Dai 1, 2, 3, 4 , Jee-Fu Huang 1, 2 , Wan-Long Chuang 1, 2 , Ming-Lung Yu 1, 2, 5, 6 1 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 6 Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Correspondence to: Ming-Lung Yu, email: fish6069@gmail.com Keywords: MICA, SNP, sMICA, liver fibrosis, CHC Received: October 15, 2016 Accepted: February 22, 2017 Published: March 06, 2017 ABSTRACT Background/Aims: Genetic variants of MHC class I polypeptide-related chain A (MICA) at rs2596542 have been associated with hepatocellular carcinoma. The linkage between serum MICA (sMICA) and liver fibrosis in chronic hepatitis C is elusive. Results: Linear regression analysis revealed that sMICA were independently correlated to α-fetoprotein (β: 0.149; 95% confidence interval [CI]: 0.001, 0.003; P = 0.007)and MICA rs2596542 GG genotype (β: 0.209; 95% CI: 0.153, 0.483; P 50 pg/mL provided a positive predictive value of 72 % in predicting advanced liver fibrosis (F3-4) and of 90% in significant fibrosis (> F2) in MICA rs2596542 A allele carriers. Materials and Methods: Serum level and single nucleotide polymorphism at rs2596542 of MICA were tested for the association with liver fibrosis in 319 biopsy proven chronic hepatitis C patients. Conclusions: Levels of sMICA were highly correlated to liver disease severity in chronic hepatitis C patients who carried the MICA rs738409 A allele. Patients possessing the genetic predisposition had a higher likelihood of progressed liver fibrosis if they expressed higher sMICA levels.

Hepatitis C virus (HCV) can replicate in peripheral blood mononuclear cells (PBMCs), which can produce interferon to defend against virus infection. We hypothesized that dynamic gene expression in PBMCs might impact the treatment efficacy of peginterferon/ribavirin in HCV patients. PBMCs were collected at baseline, 1st week and 4th week of treatment from 27 chronic HCV-1 patients with 48-week peginterferon/ribavirin therapy (screening dataset n = 7; validation dataset n = 20). A sustained virologic response (SVR) was defined as undetectable HCV RNA throughout the 24 weeks after end-of-treatment. A complete early virologic response (cEVR) was defined as negative HCV RNA at treatment week 12. Forty-three differentially expressed genes identified by Affymetrix microarray were validated by quantitative polymerase chain reaction. Thirteen genes at week 1 and 24 genes at week 4 were upregulated in the SVR group compared with the non-SVR group. We selected 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IFI44, SERPING1, IFITM3, and DDX60) at week 1 as the major components of the predictive model. This predictive model reliably stratified the responders and non-responders at week 1 (AUC = 0.89, p = 0.007 for SVR; AUC = 0.95, p = 0.003 for cEVR), especially among patients carrying the IL28B rs8099917 TT genotype (AUC = 0.89, p = 0.02 for SVR; AUC = 1.0, p = 0.008 for cEVR). The performance of this predictive model was superior to traditional predictors, including the rapid virologic response, viral load and IL28B genotype.

Background: For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naïve CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. Methods: A total of 1809 treatment-naïve chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. Results: The average medical-care cost was USD $4823 (±$2984) per treatment and $6105 (±$3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P

Background/aims The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCC) related hepatocellular carcinoma. The impact of the genetic variants and its serum levels on post-treatment cohort is elusive. Methods MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. Results Fifty-eight (8·2%) patients developed HCC, with a median follow-up period of 48·2 months (range: 6–129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5·93/1·86–26.38·61, P = 0·002) and the MICA rs2596542 A allele (HR/CI: 4·37/1·52–12·07, P = 0·002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA > 175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. Conclusions Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy., Highlights • MICA rs2596542 SNP predicts HCC development in LC patients with persistent viremia. • High sMICA levels predicts HCC occurrence in LC patients without SVR • Combining the 2 surrogate markers enhance the predicting power of HCC. The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCC) related hepatocellular carcinoma. The impact of the genetic variants and its serum levels on post-treatment cohort is elusive. We demonstrated that cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy. Combining the host genetic variants of MICA gene and serum levels of MICA proteins greatly enhanced the predictive power in the high-risk population, which provides insight for closer follow-up strategies and re-treatment priority in the era of direct antiviral agents.

Cerebral vasospasm following subarachnoid hemorrhage (SAH) has been studied in terms of a contraction of the major cerebral arteries, but the effect of cerebrum tissue in SAH is not yet well understood. To gain insight into the biology of SAH-expressing cerebrum, we employed oligonucleotide microarrays to characterize the gene expression profiles of cerebrum tissue at the early stage of SAH. Functional gene expression in the cerebrum was analyzed 2 h following stage 1-hemorrhage in Sprague-Dawley rats. mRNA was investigated by performing microarray and quantitative real-time PCR analyses, and protein expression was determined by Western blot analysis. In this study, 18 upregulated and 18 downregulated genes displayed at least a 1.5-fold change. Five genes were verified by real-time PCR, including three upregulated genes [prostaglandin E synthase (PGES), CD14 antigen, and tissue inhibitor of metalloproteinase 1 (TIMP1)] as well as two downregulated genes [KRAB-zinc finger protein-2 (KZF-2) and γ-aminobutyric acid B receptor 1 (GABA B receptor)]. Notably, there were functional implications for the three upregulated genes involved in the inflammatory SAH process. However, the mechanisms leading to decreased KZF-2 and GABA B receptor expression in SAH have never been characterized. We conclude that oligonucleotide microarrays have the potential for use as a method to identify candidate genes associated with SAH and to provide novel investigational targets, including genes involved in the immune and inflammatory response. Furthermore, understanding the regulation of MMP9/TIMP1 during the early stages of SAH may elucidate the pathophysiological mechanisms in SAH rats.

Centrosomes are organelles involved in the organization of the mitotic spindle and may also be the targets of autoantibodies in autoimmune diseases. Human Ninein (hNinein) is a centrosomal autoantigen that is identified by autoimmune patient sera. However, none of the hNinein-specific fragments recognized by the autoantibodies in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) sera have been thoroughly characterized. We thus attempted to identify the fine specificity within the hNinein protein. In this study, four recombinant proteins in two isoforms of hNinein were used as autoantigens along with immunoassays as a molecular tool to investigate the prevalence of hNinein autoreactivity and its specificity in 22 RA and 32 SLE autoimmune disease sera. The data indicated a 50% higher prevalence of isoform 4 hNinein N-terminal autoantibodies in RA sera, whereas 22% of SLE patients were autoreactive to the N-terminal of isoform 4 hNinein compared to only a small percentage of autoreactive normal sera (5%). These results showed that autoepitopes on autoantigen hNinein are restricted to the N-terminal region and that a more significant proportion of RA patients exhibited centrosome reactivity.