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The Significance of HCV Viral Load in the Incidence of HCC: a Correlation Between Mir-122 and CCL2. J Gastrointest Cancer 2021; 51:412-417. [PMID: 31385234 DOI: 10.1007/s12029-019-00281-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common cancer, the third leading cause of cancer deaths worldwide with over 500,000 people affected. It is a major cause of death in patients with chronic hepatitis C virus (HCV) infection. Overwhelming lines of epidemiological evidence have indicated that persistent infection with HCV is a major risk for the development of HCC. Although a proportion of patients with a chronic hepatitis C virus infection progress to HCC, the peak incidence of HCC associated with HCV infection has not yet occurred. AIM This review aimed to assess the impact of hepatitis C viral load on the development of HCC as a correlation between mir-122 and, the key factor in fibrogenesis, CCL2. CONCLUSION According to the detailed explanation of the role of mir-122 and CCL2 in HCV and HCC and the evidence of the inverse correlation between them, it may be concluded that HCV may affect mir-122 expression level of the hepatocytes with different patterns depending on the viral genotype. Collectively, HCV viral load alone is not sufficient to predict the HCC development and progression. Besides the quantitative evaluation of the HCV, mir-122 and CCL2 determinations should also be taken into consideration.
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Clinical Impact of Viral Load on the Development of Hepatocellular Carcinoma and Liver-Related Mortality in Patients with Hepatitis C Virus Infection. Gastroenterol Res Pract 2016; 2016:7476231. [PMID: 27656205 PMCID: PMC5021494 DOI: 10.1155/2016/7476231] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 07/15/2016] [Accepted: 08/03/2016] [Indexed: 01/16/2023] Open
Abstract
Aim. This study aimed to assess clinical impact of hepatitis C viral load on the development of hepatocellular carcinoma (HCC) and liver-related mortality in HCV-infected patients. Methods. A total of 111 subjects with chronic HCV infection who were available for serum quantitation of HCV RNA were recruited in this retrospective cohort. Cox-proportional hazards models were used to calculate hazard ratio (HR) of developing HCC and liver-related mortality according to serum HCV RNA titers. Results. HCC was developed in 14 patients during follow-up period. The cumulative risk of HCC development was higher in subjects with high HCV RNA titer (log HCV RNA IU/mL > 6) than subjects with low titer (log HCV RNA IU/mL ≦ 6) (HR = 4.63, P = 0.032), giving an incidence rate of 474.1 and 111.5 per 10,000 person-years, respectively. Old age (HR = 9.71, P = 0.014), accompanying cirrhosis (HR = 19.34, P = 0.004), and low platelet count (HR = 13.97, P = 0.009) were other independent risk factors for the development of HCC. Liver-related death occurred in 7 patients. Accompanying cirrhosis (HR = 6.13, P = 0.012) and low albumin level (HR = 9.17, P = 0.002), but not HCV RNA titer, were significant risk factors related to liver-related mortality. Conclusion. Serum HCV RNA titer may be considered an independent risk factor for the development of HCC but not liver-related mortality.
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Hung CH, Chen CH, Lee CM, Hu TH, Lu SN, Wang JH, Huang CM. Role of viral genotypes and hepatitis B viral mutants in the risk of hepatocellular carcinoma associated with hepatitis B and C dual infection. Intervirology 2013; 56:316-24. [PMID: 23838434 DOI: 10.1159/000350738] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 03/07/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND/AIMS The independent and interactive effects of hepatitis B virus (HBV) and hepatitis C virus (HCV) factors on the development of hepatocellular carcinoma (HCC) in chronic HBV/HCV dually-infected patients remain unclear. METHODS In a cross-sectional and case-controlled study, the HBV and HCV loads and genotypes and the sequences of pre-S and precore/core promoter regions were determined in 146 HCC patients and 167 chronic carriers with HBV/HCV dual infection. RESULTS Age (odds ratio (OR) 1.1), male sex (OR 2.3), pre-S deletion (OR 5.0), A1762T/G1764A mutant (OR 2.5), HCV genotype-1 (OR 2.4) and platelet count <15 × 10(4)/μl (OR 1.9) were independently associated with HCC by stepwise logistic regression analysis. Patients with combined HBV mutations (pre-S deletion and A1762T/G1764A mutant) and HCV genotype-1 had a 39-fold increased risk of developing HCC compared to those with A1762T/G1764A and pre-S wild-type strains and HCV genotype non-1. In the nested case-control study, patients with HCC had a higher HBV DNA level (p < 0.001), a higher frequency of pre-S deletion (p < 0.001) and A1762T/G1764A mutant (p = 0.005), a lower HCV RNA level (p = 0.012) and a higher prevalence of HCV genotype-1 (p = 0.002) than those without. CONCLUSIONS Pre-S deletion, A1762T/G1764A mutation and HCV genotype-1 are important in hepatocarcinogenesis in chronic HBV/HCV dual infection.
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Affiliation(s)
- C-H Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan, ROC.
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Cho EJ, Jeong SH, Han BH, Lee SU, Yun BC, Park ET. Hepatitis C virus (HCV) genotypes and the influence of HCV subtype 1b on the progression of chronic hepatitis C in Korea: a single center experience. Clin Mol Hepatol 2012; 18:219-24. [PMID: 22893873 PMCID: PMC3415883 DOI: 10.3350/cmh.2012.18.2.219] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 04/18/2012] [Accepted: 04/24/2012] [Indexed: 12/12/2022] Open
Abstract
Background/Aims There is some controversy regarding whether or not hepatitis C virus (HCV) subtype 1b is more influential than non-1b subtypes on the progression of chronic hepatitis (CH) C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Methods We retrospectively analyzed 823 patients with chronic HCV infection, including 443 CH patients, 264 LC patients, and 116 HCC patients, who were HCV RNA positive and HBsAg negative. These patients had not received any prior treatment with either interferon alone or a combination of interferon and ribavirin. Results HCV subtypes 1b (51.6%) and 2a/2c (39.5%) were the two most common genotypes. The proportions of genotypes 2 (2a/2c, 2b, and 2) and 3 were 45.8% and 1.1%, respectively. One case of genotype 4 was found. HCV subtype 1b (47.3%) was less common than the non-1b subtypes (52.7%) in non-LC patients, but its proportion (56.9%) was higher than that of non-1b subtypes (43.1%) in LC patients (P=0.006). The proportions of patients with HCV subtype 1b did not differ significantly between the LC (55.3%) and HCC (60.3%) groups. Older age, male gender, and the relative progression of liver damage (non-LC vs. compensated LC vs. decompensated LC) were significant risk factors for HCC, with odds ratios of 1.081 (95% confidence interval [CI], 1.056-1.106), 5.749 (95% CI, 3.329-9.930), and 2.895 (95% CI, 2.183-3.840), respectively. HCV subtype 1b was not a significant risk factor for HCC (odds ratio, 1.423; 95% CI, 0.895-2.262). Conclusions HCV subtypes 1b and 2a/2c were the two most common HCV genotypes. HCV subtype 1b seemed to be more influential than non-1b subtypes on the progression of CH to LC, but not on the development of HCC from LC.
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Affiliation(s)
- Eun Ju Cho
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
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Brahim I, Akil A, Mtairag EM, Pouillot R, Malki AE, Nadir S, Alaoui R, Njouom R, Pineau P, Ezzikouri S, Benjelloun S. Morocco underwent a drift of circulating hepatitis C virus subtypes in recent decades. Arch Virol 2011; 157:515-20. [PMID: 22160625 DOI: 10.1007/s00705-011-1193-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 12/01/2011] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) isolates circulating in Morocco are poorly documented. To determine the subgenotype distribution of HCV in chronically infected patients, serum samples from 185 anti-HCV-positive patients were analyzed. Determination of the HCV genotype and subtype was performed by sequencing the 5'UTR, NS5B and core regions. According to the NS5B phylogeny, the HCV strains primarily belonged to subtypes 1b (75.2%), 2i (19.1%) and 2k (2.8%). Using a Bayesian approach, the mean date of appearance of the most recent common ancestor was estimated to be 1910 for HCV-1b and 1854 for HCV-2i. Although it is currently the most frequent genotype in Morocco and the dominant form in hepatocellular carcinoma, it thus appears that HCV-1b was introduced into the population subsequently to HCV-2i.
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Affiliation(s)
- Ikram Brahim
- Virology Unit, Viral Hepatitis Laboratory, Pasteur Institute of Morocco, 1, Place Louis Pasteur, 20360 Casablanca, Morocco
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Wang YZ, Wang WB, Cao MM, Wang W, Zhao LJ, Xu G, Ren H, Qi ZT. Function of nonstructural 5A protein of genotype 2a in replication and infection of HCV with gene substitution. World J Gastroenterol 2011; 17:3398-406. [PMID: 21876632 PMCID: PMC3160566 DOI: 10.3748/wjg.v17.i29.3398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Revised: 02/26/2011] [Accepted: 03/05/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the function of Nonstructural 5A (NS5A) protein of genotype 2a (JFH1) in the replication and infection of hepatitis C virus (HCV).
METHODS: Intergenotypic chimera FL-J6JFH/J4NS5A was constructed by inserting NS5A gene from 1b stain HC-J4 by the overlapping polymerase chain reaction (PCR) method and the restriction enzyme reaction. In vitro RNA transcripts of chimera, prototype J6JFH and negative control J6JFH1 (GND) were prepared and transfected into Huh-7.5 cells with liposomes. Immunofluorescence assay (IFA), fluorescence quantitative PCR and infection assay were performed to determine the protein expression and gene replication in Huh-7.5 cells.
RESULTS: The HCV RNA levels in FL-J6JFH/J4NS5A chimera RNA transfected cells were significantly lower than the wild type at any indicated time point (2.58 ± 5.97 × 106vs 4.27 ± 1.72 × 104, P = 0.032). The maximal level of HCV RNA in chimera was 5.6 ± 1.8 × 104 GE/μg RNA at day 34 after transfection, while the wild type reached a peak level at day 13 which was 126 folds higher (70.65 ± 14.11 × 105vs 0.56 ± 0.90 × 105, P = 0.028). HCV proteins could also be detected by IFA in chimera-transfected cells with an obviously low level. Infection assay showed that FL-J6JFH/J4NS5A chimera could produce infectious virus particles, ranging from 10 ± 5 ffu/mL to 78.3 ± 23.6 ffu/mL, while that of FL-J6JFH1 ranged from 5.8 ± 1.5 × 102 ffu/mL to 2.5 ± 1.4 × 104 ffu/mL.
CONCLUSION: JFH1 NS5A might play an important role in the robust replication of J6JFH1. The establishment of FL-J6JFH/J4NS5A provided a useful platform for studying the function of other proteins of HCV.
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Sistayanarain A, Kunthalert D, Vipsoongnern Y. A shift in the hepatitis C virus genotype dominance in blood donor samples from Thailand. Mol Biol Rep 2010; 38:4287-90. [PMID: 21113670 DOI: 10.1007/s11033-010-0552-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2010] [Accepted: 11/17/2010] [Indexed: 12/22/2022]
Abstract
Hepatitis C virus (HCV) can be classified into six major genotypes. The HCV genotypes variability accounts for its geographical distribution, its responses to treatments and the clinical outcomes. The aim of this study was to determine the distribution of HCV genotypes among volunteer blood donors in Thailand. Samples from 135 anti-HCV positive blood donors were analyzed. HCV RNA and genotyping was carried out using nested polymerase chain reaction (PCR) and genotype-specific primer PCR for a portion of the core region. HCV RNA was detected in 109 samples (80.7%). Genotype analysis demonstrated four different genotypes. The most common was genotype 3a (36.7%), followed by genotype 6 (29.4%), 1a (19.3%), 1b (6.4%) and mixed infection (1.8%). Seven samples were untyped (6.4%) in the present study. In several previous reports, the prevalence found in Thailand was HCV genotypes 3, 1 and 6. The present results show an increasing importance of the genotype 6 in HCV infections. This study has also described for the first time in Thailand mixed infections of HCV genotypes.
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Affiliation(s)
- Anchalee Sistayanarain
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.
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Nakamoto S, Imazeki F, Fukai K, Fujiwara K, Arai M, Kanda T, Yonemitsu Y, Yokosuka O. Association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development. J Hepatol 2010; 52:72-8. [PMID: 19910070 DOI: 10.1016/j.jhep.2009.10.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Revised: 07/22/2009] [Accepted: 08/04/2009] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS To determine whether amino acid mutations in the core region of hepatitis C virus (HCV) genotype 1 are associated with response to interferon (IFN) therapy and development of hepatocellular carcinoma (HCC). METHODS We followed up 361 patients (median duration, 121 months), and IFN monotherapy was administered to 275 (76%) [sustained virological response (SVR) rate, 26.5%]. Using pretreatment sera, mutations at core residues 70 and 91 were analyzed [double wild (DW)-type amino acid pattern: arginine, residue 70; leucine, residue 91]. RESULTS A low aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and low HCV load were independently associated with SVR, but core mutations were not. During follow-up, 12 of 81 (14.8%) patients with the DW-type pattern and 52 of 216 (24.1%) patients with non-DW-type pattern developed HCC (p=0.06, Breslow-Gehan-Wilcoxon test). Multivariate analysis with the Cox proportional-hazards model revealed the following independent risk factors for HCC: male gender [p<0.0001; risk ratio (RR), 3.97], older age (p<0.05; RR, 2.08), advanced fibrosis (p<0.0001; RR, 5.75), absence of SVR (p<0.01; RR, 10.0), high AST level (p<0.01; RR, 2.08), high AST/ALT ratio (p<0.01; RR, 2.21), and non-DW-type pattern (p<0.05; RR, 1.96). In patients with F0-F2 fibrosis at entry, non-DW-type was likely to lead to cirrhosis (p=0.051). CONCLUSIONS In HCV genotype 1 patients, HCC risk could be predicted by studying core mutations, response to IFN, and host factors like age, gender, and liver fibrosis.
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Affiliation(s)
- Shingo Nakamoto
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ward, Chiba City, Chiba 260-8670, Japan
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Ikeda K, Kobayashi M, Someya T, Saitoh S, Hosaka T, Akuta N, Suzuki F, Suzuki Y, Arase Y, Kumada H. Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study. J Viral Hepat 2009; 16:437-43. [PMID: 19226331 DOI: 10.1111/j.1365-2893.2009.01085.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
An impact of serum hepatitis B virus (HBV) DNA on hepatocarcinogenesis has not been investigated in a cohort of patients with non-B, non-C cirrhosis. Eighty-two consecutive Japanese patients with cirrhosis, who showed negative hepatitis B surface antigen and negative anti-hepatitis C virus, were observed for a median of 5.8 years. Hepatitis B virus core (HBc) region and HBx region were assayed with nested polymerase chain reaction. Both of HBc and HBx DNA were positive in 9 patients (11.0%) and both were negative in 73. Carcinogenesis rates in the whole patients were 13.5% at the end of the 5th year and 24.6% at the 10th year. The carcinogenesis rates in the patients with positive DNA group and negative DNA group were 27.0% and 11.8% at the end of the 5th year, and 100% and 17.6% at the 10th year, respectively (P = 0.0078). Multivariate analysis showed that men (P = 0.04), presence of HBc and HBx DNA (hazard ratio: 8.25, P = 0.003), less total alcohol intake (P = 0.010), older age (P = 0.010), and association of diabetes (P = 0.005) were independently associated with hepatocellular carcinogenesis. Existence of serum HBV DNA predicted a high hepatocellular carcinogenesis rate in a cohort of patients with non-B, non-C cirrhosis.
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Affiliation(s)
- K Ikeda
- Department of Hepatology, Toranomon Hospital, Minato-ku, Tokyo, Japan.
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Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis. J Hepatol 2009; 50:1142-54. [PMID: 19395111 DOI: 10.1016/j.jhep.2009.01.019] [Citation(s) in RCA: 159] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 01/13/2009] [Accepted: 01/26/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Hepatitis C virus (HCV) is a known risk factor for hepatocellular carcinoma (HCC), but whether the risk varies among patients infected with different HCV genotypes is still controversial. We performed a meta-analysis to clarify whether the genotype 1b is associated with a higher risk of HCC than other genotypes. METHODS We identified 57 relevant papers through a literature search to December 2007 but, since age could represent a major confounder, we focused the meta-analysis on the 21 studies presenting age-adjusted risk estimates for HCV genotype 1b vs. other genotypes. We used random-effects models with the DerSimonian-Laird method and assessed heterogeneity between studies and publication bias. RESULTS Patients infected with HCV genotype 1b have almost double the risk to develop HCC than those infected with other genotypes (Relative Risk (95% Confidence Intervals) = 1.78(1.36-2.32)). The pooled risk estimate was somewhat lower when we restricted the analysis to the eight studies conducted in patients with liver cirrhosis (1.60;1.07-2.39) or considering the 36 studies presenting only crude data (1.63;1.30-2.06). In seven studies excluding patients with liver cirrhosis, the RR (95% CI) increased to 2.46(1.69-3.59). CONCLUSIONS This meta-analysis suggests that HCV genotype 1b plays an important role in HCC development, especially in patients with early stage liver disease.
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Hung CH, Chen CH, Lee CM, Wu CM, Hu TH, Wang JH, Yen YH, Lu SN. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J Viral Hepat 2008; 15:58-65. [PMID: 18088246 DOI: 10.1111/j.1365-2893.2007.00892.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
NS5A and E2 proteins of the hepatitis C virus (HCV) have the potential to repress protein kinase R (PKR) that exerts a tumour suppressor function. We investigated the relationship between amino acid variations in the NS5A-PKR-binding domain and E2-PKR-eIF2alpha phosphorylation homology domain (PePHD) region and the development of hepatocellular carcinoma (HCC) in chronic HCV-1b patients. In a cross-sectional, hospital-based setting, we compared the amino acid sequences of NS5A-PKR-binding domain and E2-PePHD in the sera of 104 chronic hepatitis, 44 cirrhosis and 96 HCC patients. The nucleotide sequences were inferred by direct sequencing of the amplified HCV products and deduced amino acid were compared with the sequence of HCV-J. By univariate analysis, old age, lower viral load, fewer amino acid substitutions in the NS5A-PKR-binding domain (codons 2209-2274) and the interferon sensitivity-determining region (ISDR; codons 2209-2248), and wild-type amino acid at codon 2209 and codon 2240 was significantly correlated with HCC, whereas substitutions in the E2-PePHD was not. Patients with a mutated-type (> or = 4) NS5A-ISDR had a lower prevalence of HCC than those with intermediate or wild type (P < 0.05). Based on stepwise logistic regression analysis, age [odds ratio (OR): 1.132, P < 0.001], viral load (OR: 0.305, P < 0.001) and mutated-type ISDR (OR: 0.137, P = 0.001) were independently associated with HCC. In conclusion, NS5A-ISDR variations may play an important role in the development of HCV-related HCC.
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Affiliation(s)
- C-H Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Lee CM, Lu SN, Hung CH, Tung WC, Wang JH, Tung HD, Chen CH, Hu TH, Changchien CS, Chen WJ. Hepatitis C virus genotypes in southern Taiwan: prevalence and clinical implications. Trans R Soc Trop Med Hyg 2006; 100:767-74. [PMID: 16443243 DOI: 10.1016/j.trstmh.2005.10.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2005] [Revised: 10/20/2005] [Accepted: 10/21/2005] [Indexed: 12/20/2022] Open
Abstract
The role of hepatitis C virus (HCV) genotypes in the development of hepatocellular carcinoma (HCC) is still controversial. To determine the distribution and clinical implications of HCV genotypes in southern Taiwan, we analysed 418 patients with chronic HCV infections. HCV genotypes were determined using an HCV Line Probe Assay. The predominant HCV genotype was 1b (45.5%), followed by 2a/2c (30.9%) and 2b (6.9%). The prevalence of genotype 1b in HCC patients (60.3%) was significantly higher than in those with liver cirrhosis (38.7%) and chronic hepatitis (38.7%) (P=0.003 and P<0.001, respectively). Patients with chronic HCV 2a/2c infection had higher alanine aminotransferase (ALT) levels than those with chronic HCV 1b infection (P<0.001). Univariate analysis revealed that disease severity was significantly correlated with older age, genotype 1b, lower ALT levels and lower viral load. Based on multiple logistic regression analysis, after adjusting for age and serum HCV RNA levels, HCV 1b infection was still a significant risk factor for HCC. In conclusion, the predominant genotypes in southern Taiwan were 1b and 2a/2c, and disease severity was associated with genotype 1b.
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Affiliation(s)
- Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.
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Lee CM, Hung CH, Lu SN, Wang JH, Tung HD, Huang WS, Chen CL, Chen WJ, Changchien CS. Viral etiology of hepatocellular carcinoma and HCV genotypes in Taiwan. Intervirology 2005; 49:76-81. [PMID: 16166793 DOI: 10.1159/000087267] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas of the world. Hepatitis B virus infection is associated with HCC. However, hepatitis C virus (HCV) infection plays an increasingly more important role in the development of HCC and is associated with more than 30% of HCC in Taiwan. The prevalence of HCV infection and HCV genotypes vary in different geographic areas. The prevalence of HCV genotype 1b (HCV-1b) was around 50-70% in Taiwan and even varied in different townships. In addition to host factors, HCV genotypes may be associated with the development of HCC. In our study, the prevalence of HCV-1b in patients with HCC was significantly higher than in those with liver cirrhosis and chronic hepatitis; multivariate analysis revealed that the disease severity was significantly correlated with age and HCV-1b. Furthermore, HCV-1b was associated with a lower response rate to interferon (IFN) therapy than HCV-2. Our study has demonstrated that mutations in the IFN sensitivity-determining region, spanning nucleotides 2,209-2,248 in the NS5A region, correlate with the sustained virological response to combination therapy with IFN and ribavirin in patients with chronic HCV-1b infection in Taiwan. A third-generation enzyme immunoassay for antibody to HCV can be used to predict viremia and monitor the virological response.
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Affiliation(s)
- Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan (ROC).
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Sawada K, Masaki N, Hayashi S, Zeniya M, Ishikawa T, Takahashi H, Ohnishi K, Fukunaga K, Hara N, Yamamoto T, Hada T, Toda G. Immunomodulatory effects of selective leucocytapheresis as a new adjunct to interferon-alpha2b plus ribavirin combination therapy: a prospective study in patients with high plasma HCV viraemia. J Viral Hepat 2005; 12:274-82. [PMID: 15850468 DOI: 10.1111/j.1365-2893.2005.00577.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Efficacy of interferon-alpha2b (IFN) + ribavirin (IFN/RBV) combination in patients with high plasma hepatitis C virus (HCV) is very poor. Dysregulated CD4+ /CD8+ T cells is involved in both impaired cell-mediated immunity and resistance to IFN. Adsorptive granulocytes and monocytes apheresis (GMA) can remove infected leucocytes which are extrahepatic HCV reservoirs and also has been associated with intriguing immunomodulation and increases in CD4+ T cells. Our aim was to see if GMA enhances the efficacy of IFN/RBV. Twenty-four patients, 13 IFN resistant and 11 IFN naive were enrolled. Seventeen were genotype 1b and 7 were 2a or 2b. Mean plasma HCV-RNA was 612.9 (100-850) kIU/mL and alanine aminotransferase, 108 (41-373) U/L. GMA was performed with Adacolumn at one session/day for five consecutive days and IFN/RBV was started within 24 h after the last GMA session. Daily 6 million units of IFN, six times/week for 2 weeks and then three times/week for 22 weeks were given with RBV (600-800 mg/day/patient). Patients were followed for 6 months. GMA was associated with a significant increase in lymphocyte counts, complement activation fragment C3a and falls in tissue necrosis factor-alpha, and IL-8 produced by peripheral blood leucocytes. At week 24, 20 of 24 patients (83%) were HCV negative and by end of follow-up (week 49), the remission was sustained in 14 of 24 patients (58%) including 100% of patients with 2a or 2b. In conclusion, enhanced efficacy of IFN/RBV following GMA might be attributed to a more efficient immune function and a renewed IFN signaling towards HCV.
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Affiliation(s)
- K Sawada
- Department of Gastroentrology, Fujimoto Hospital Medicine, Osaka 583-0857, Japan.
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Mukaide M, Tanaka Y, Kakuda H, Fujiwara K, Kurbanov F, Orito E, Yoshioka K, Fujise K, Harada S, Kozaki T, Takemura K, Hikiji K, Mizokami M. New combination test for hepatitis C virus genotype and viral load determination using Amplicor GT HCV MONITOR test v2.0. World J Gastroenterol 2005; 11:469-75. [PMID: 15641128 PMCID: PMC4250793 DOI: 10.3748/wjg.v11.i4.469] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a new sensitive and inexpensive hepatitis C virus (HCV) combination test (HCV Guideline test) that enables the determination of HCV genotypes 1, 2 and 3, and simultaneous determination of HCV viral load using commercial Amplicor GT HCV MONITOR test v2.0 (microwell version).
METHODS: The HCV Guideline test used the PCR product generated in commercial Amplicor GT HCV Monitor test v2.0 for viral load measurement using microwell plate version of Amplicor HCV Monitor and also captured on separate plates containing capture probes and competitive oligonucleotide probes specific for HCV genotypes 1, 2 and 3, The HCV genotype was subsequently determined using the biotin-labeled PCR product and five biotin-labeled HCV-specific probes.
RESULTS: The sensitivity of the HCV Guideline test was 0.5 KIU/mL. Specificity of the HCV Guideline test was confirmed by direct sequencing of HCV core region and molecular evolutionary analyses based on a panel of 31 samples. The comparison of the HCV Guideline test and an in-house HCV core genotyping assay using 252 samples from chronic hepatitis C patients indicated concordant results for 97.2% of samples (59.5% genotype 1, 33.7% genotype 2, 6.0% genotype 3, and 0.8% mixed genotypes). Similarly, the HCV Guideline test showed concordance with a serological test, and the serological test failed to assign any serotype in 12.7% of the samples, indicating a better sensitivity of the HCV Guideline test.
CONCLUSION: Clinically, both viral load and genotypes (1, 2 and 3) have been found to be major predictors of antiviral therapy outcome regarding chronic hepatitis C based on guidelines and they are, in normal circumstances, performed as separate stand-alone assays. The HCV Guideline test is a useful method for screening large cohorts in a routine clinical setting for determining the treatment regimen and for predicting the outcome of antiviral therapy of chronic hepatitis C.
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Affiliation(s)
- Motokazu Mukaide
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Science, Kawasumi, Mizuho, Nagoya 467-8601, Japan
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16
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Hnatyszyn HJ. Chronic Hepatitis C and Genotyping: The Clinical Significance of Determining HCV Genotypes. Antivir Ther 2005. [DOI: 10.1177/135965350501000118] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Chronic hepatitis C, attributed to infection with hepatitis C virus (HCV), is a global health problem. The overall prevalence of viral hepatitis worldwide is estimated to be 3–5% with over 175 million people infected with HCV. Clinically, HCV can establish a persistent, chronic infection contributing to progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC), requiring intensive treatment regimens, possible liver transplantation and long-term care. Due to the chronic nature of HCV infection and the tremendous burden on healthcare resources, clinicians and laboratorians have looked for key epidemiological, pathological and viral characteristics that may provide insight into disease progression, severity and response to therapy to permit the administration of effective therapeutic regimens as well as long-term management of infected individuals. Determination of viral genotype has been identified as one parameter that could provide direction in the clinical management of patients with chronic HCV infections. The following review provides background on determination of HCV genotypes and the relevance of viral genome characterization in the current clinical setting.
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Affiliation(s)
- H James Hnatyszyn
- Bayer Institute for Clinical Investigation (BICI), Bayer HealthCare – Diagnostics Division, Berkeley, CA, USA
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Abstract
The number of papers published in the topic of hepatocellular carcinoma (HCC) increased remarkably from last year. The prevalence of chronic hepatitis C infection has increased the incidence of HCC. However, studies confirm that obesity and nonalcoholic fatty liver disease are important factors for the development of HCC in the United States. Alpha-fetoprotein is the most widely used tumor marker, but has poor diagnostic accuracy and ethnic variability. Using proteonomic genome analysis, new candidate tumor markers have been identified but await validation. Dynamic gadolinium magnetic resonance imaging seems to be more sensitive than spiral computed tomography scan for the identification of HCC, and seems to be modality of choice in most centers. Transplantation offers the best long-term option for patients with HCC, but in a certain group of patients without portal hypertension and well-preserved liver function, surgical resection is an acceptable option. A large study from Europe confirms the utility of resection in some patients with early HCC. However, most patients are not candidates for curative intervention. A meta-analysis and a randomized, controlled trial showed that chemoembolization offers a survival advantage in selected patients (Child class A and B) with nonresectable HCC. Finally, chemoprevention in patients with chronic hepatitis C infection with interferon is a promising strategy to prevent HCC.
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Affiliation(s)
- Jorge A Marrero
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109-0362, USA.
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Hao CQ, Feng ZH, Zhou YX, Nie QH, Li JG, Jia ZS, Liang XS, Xie YM, Cao YZ, Kang WZ. Construction, package and identification of replication-deficient recombinant adenovirus expression vector of HCV C. Shijie Huaren Xiaohua Zazhi 2003; 11:144-147. [DOI: 10.11569/wcjd.v11.i2.144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct a replication-deficient recombinant adenovirus expression vector of HCV C.
METHODS: The HCV core gene was cloned at the downstream of CMV promoter of the adenoviral shuttle plasmid pAd. CMV-link. 1, and the resultant recombinant plasmid pAd. HCV-C was cotransfected into 293 cell together with plasmid pJM17 containing adenoviral genome, then the adenovirus expression vector was obtained, and identified by infecting test, electronic microscope observation and PCR co-amplification. The plasmid pAd. HCV-C was identified by endonuclease, PCR and sequencing. The expressive activity of adenovirus vector was identified by immunofluorescence and Western blot.
RESULTS: HCV core gene in the inserted DNA of pAd. HCV-C was confirmed by endonuclease, PCR and sequencing. Results of infecting test, electronic microscopic observation and PCR co-amplification showed that the adenovirus vector had been constructed successfully. Expression of HCV core antigen was proved in the HepG2 cells by immunofluorescence and Western blot.
CONCLUSION: The replication-deficient recombinant adenovirus vector can express HCV core antigen in HepG2 cells. This study established a foundation for further study on HCV vaccines and gene therapy for hepatitis C.
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Dizer U, Beker CM, Yavuz I, Ortatatli M, Ozguven V, Pahsa A. Minimal change disease in a patient receiving IFN-alpha therapy for chronic hepatitis C virus infection. J Interferon Cytokine Res 2003; 23:51-4. [PMID: 12639299 DOI: 10.1089/10799900360520450] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic syndromes. The principal types of renal disorders associated with chronic HCV infection are cryoglobulinemia or noncryoglobulinemic membranoproliferative glomerulonephritis (MPGN). Interferon-alpha (IFN-alpha) may precipitate or exacerbate the occurrence of MPGN. Our patient was a 32-year-old man who tested positive for HCV in July 1997. The patient was treated with IFN-alpha in another medical center for 6 months because his liver biopsy showed chronic active hepatitis. In December 1998, he applied to our clinic for a follow-up examination. The level of aspartate aminotransferase (AST) was 44 U/L, and that of alanine aminotransferase (ALT) was 69 U/L. HCV RNA was positive in serum, and chronic HCV infection was detected by liver biopsy. IFN-alpha therapy (5 million U/day) was administered for 6 months longer. In May 1999, the patient came to our polyclinic with edema of the feet and legs. We detected proteinuria, serum cholesterol of 269 mg/dl, AST of 50 U/L, ALT of 41 U/L, serum total protein of 3.4 g/dl, serum albumin of 1.2 g/dl, positive cryoglobulin, and urine protein of 9.84 g/day. Cryoglobulinemic MPGN was suspected and kidney biopsy was performed, resulting in a diagnosis of minimal change disease (MCD).
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Affiliation(s)
- Ufuk Dizer
- Department of Infectious Diseases and Clinical Microbiology, Gülhane Military Medical Academy, Ankara, Turkey.
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