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1
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Baig S, Berikkara A, Khalid R, Subhan SA, Abbas T, Abidi SH. In silico analysis of the effect of HCV genotype-specific polymorphisms in Core, NS3, NS5A, and NS5B proteins on T-cell epitope processing and presentation. Front Microbiol 2025; 15:1498069. [PMID: 39881992 PMCID: PMC11774985 DOI: 10.3389/fmicb.2024.1498069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/20/2024] [Indexed: 01/31/2025] Open
Abstract
Background HCV genotypes are 30-35% polymorphic at the nucleotide level, while subtypes within the same genotype differ by nearly 20%. Although previous studies have shown the immune escape potential of several mutations within the HCV proteins, little is known about the effect of genotype/subtype-specific gene polymorphism on T-cell immunity. Therefore, this study employed several in silico methods to examine the impact of genotype/subtype-specific polymorphisms in Core, NS3, NS5A, and NS5B sequences on T cell epitope processing and HLA-epitope interactions. Methods For this study, 8,942, 17,700, 14,645, and 3,277 HCV Core, NS3, NS5A, and NS5B sequences, respectively, from eight genotypes and 21 subtypes were retrieved from the Los Alamos HCV Database. Next, the NetCTL tool was employed to predict Cytotoxic T Lymphocyte (CTL) epitopes based on combined proteasomal cleavage, TAP efficacy, and HLA class I receptor binding scores. PEP-FOLD was used to model selected epitopes, followed by peptide-HLA docking using HPEPDOCK. Finally, molecular dynamics simulations were conducted for 200 ns using Desmond software to analyze differences in HLA-epitope (from different HCV genotypes) interaction kinetics and dynamics. Results A total of 3,410, 8,054, 6,532, and 14,015 CTL epitopes were observed in the HCV Core, NS3, NS5A, and NS5B sequences, respectively. Significant genotype/subtype-specific variations in CTL values and docking scores were observed among NS3, NS5A, and NS5B proteins. In silico results reveal that epitopes from genotype 6b (NS3), 6d/r (NS5B), 6o and 6 k (NS5A) exhibit higher immunogenicity than other genotypes, forming more energetically stable complexes with host receptors. These epitopes, compared to those from the same positions but different genotypes, showed binding energies of -144.24 kcal/mol, -85.30 kcal/mol, and - 43 kcal/mol, respectively. Over a 200 ns MD simulation, GT 6b and 6d/r epitopes displayed up to a 40% stronger binding energy with the HLA receptor. These findings suggest that patients infected with GT 6 may experience enhanced T cell responsiveness and broader immunogenicity. Conclusion Our study suggests that genotype/subtype-specific polymorphism in HCV may result in altered immune responses by modulating T-cell epitope processing and interaction with HLA receptors. Further experimental studies can be performed to confirm the effect of genotype/subtype-specific polymorphisms on T cell-mediated immune response.
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Affiliation(s)
- Samina Baig
- Department of Microbiology, University of Karachi, Karachi, Pakistan
- Dow Institute of Medical Technology, Dow University of Health Sciences, Karachi, Pakistan
| | - Assel Berikkara
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Ramsha Khalid
- Department of Biochemistry, University of Karachi, Karachi, Pakistan
| | - Syed A. Subhan
- Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Tanveer Abbas
- Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Syed Hani Abidi
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
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2
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Sadeghi S, Davari M, Asli E, Gharibzadeh S, Vaziri F, Jamnani FR, Fateh A, Siadat SD. Effect of IL15 rs10833 and SCARB1 rs10846744 on virologic responses in chronic hepatitis C patients treated with pegylated interferon-α and ribavirin. Gene 2017; 630:28-34. [PMID: 28827115 DOI: 10.1016/j.gene.2017.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/22/2017] [Accepted: 08/03/2017] [Indexed: 12/20/2022]
Abstract
The scavenger receptor type B class I (SCARBI) is known to be involved in the entry of hepatitis C virus (HCV) into the host, while interleukin-15 (IL15) is an important cytokine in both the innate and acquired immune responses against HCV infection. We investigated the association of IL15 rs10833 or SCARB1 rs10846744 polymorphisms with treatment responses in patients with chronic HCV (CHC). SCARB1 rs10846744 and IL15 rs10833 were identified in 365 treatment-naïve CHC patients through genotyping by TaqMan® Real-Time PCR and PCR-restriction fragment length polymorphism (RFLP), respectively. Of these 365 CHC treatment-naïve patients, rapid virological response (RVR), complete early virological response (cEVR), and sustained virological response (SVR) were observed in 53.2%, 76.4%, and 66.0% of the patients, respectively. Multivariate logistic regression analysis revealed that RVR was associated with sex (P=0.016), aspartate aminotransferase (AST) (P=0.026), IL15 rs10833 (AA) genotype (P<0.001), and SCARB1 rs10846744 (CC) genotype (P<0.001), while there was a relationship between alanine aminotransferase (ALT) (P=0.013) and IL15 rs10833 (AA) genotype (P<0.001) with cEVR. Age (<40years) (P=0.001), AST (P=0.029), ALP (P=0.028), HCV genotypes (P=0.005), HCV viral load (P=0.026), IL15 rs10833 (AA) genotype (P<0.001), and SCARB1 rs10846744 (CC) genotype (P=0.001) were strongly associated with SVR. In conclusion, the SCARB1 rs10846744 (CC) and IL15 rs10833 (AA) genotypes can be considered as powerful predictors of treatment responses in CHC patients treated with an interferon-based therapy.
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Affiliation(s)
- Sahar Sadeghi
- Department of Biology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Mehdi Davari
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Esmaeil Asli
- Department of Human Bacterial Vaccine Production, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran
| | - Safoora Gharibzadeh
- Research Centre for Emerging and Reemerging Infectious Diseases, Pasteur Institute of Iran, Tehran, Iran; Department of Epidemiology and Biostatistics, Pasteur Institute of Iran, Tehran, Iran
| | - Farzam Vaziri
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Rahimi Jamnani
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran.
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
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Cai Q, Zhang X, Lin C, Shao X, Guan Y, Deng H, Wei M, Huang M, Ren Z, Lu L, Mei Y, Xu M, Zhu J, Shi H, Lin G, Liu Y, Hu F, Luo Q, Lan Y, Guo F, Zhao Z, Gao Z. 24 versus 48 Weeks of Peginterferon Plus Ribavirin in Hepatitis C Virus Genotype 6 Chronically Infected Patients with a Rapid Virological Response: A Non-Inferiority Randomized Controlled Trial. PLoS One 2015; 10:e0140853. [PMID: 26509605 PMCID: PMC4624894 DOI: 10.1371/journal.pone.0140853] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 09/29/2015] [Indexed: 12/27/2022] Open
Abstract
Objectives The optimal treatment of hepatitis C virus (HCV) genotype 6 is unclear owing to its limited geographic distribution. Because of a high predictive value of rapid virological response (RVR) for sustained virological response (SVR), we conducted an open-label randomized controlled trial to compare 24- and 48-week peginterferon/ribavirin combination therapy for patients with HCV genotype 6 in Southern China who achieved an RVR. Methods and Findings Treatment-naive, non-cirrhotic patients with chronic hepatitis C genotype 6 were treated with pegylated interferon α-2a (180 μg/week) and ribavirin (800–1,200 mg, according to weight) for 4 weeks. Patients who achieved an RVR, which was defined as HCV RNA negativity at week 4 (<50 IU), were randomized to receive either an additional 20 or 44 weeks of treatment (24- and 48-week treatment groups, respectively). The primary outcome measure was SVR. From January 2011 to June 2014, 152(152/210, 72.4%) patients with HCV genotype 6a and RVR were randomized 1:1 to the 24- or 48-week treatment group. The SVR rates in the 24- and 48-week groups in the intention-to-treat analysis were 90.8% (69/76) and 88.2% (67/76), respectively; those in the per-protocol analysis were 95.7% (67/70) and 97.0% (64/66), respectively. More patients in the 48-week group had anemia (46.1% vs. 28.9%, P = 0.03), but other adverse events were comparable between the groups. The limitation of the present study was that only patients from Southern China were enrolled which may inhibit the extensive application of the findings. Conclusion Twenty-four weeks of peginterferon/ribavirin combination therapy was non-inferior to 48 weeks in patients with HCV genotype 6a in Southern China who achieved an RVR. Trial Registration ClinicalTrials.gov NCT01263860
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Affiliation(s)
- Qingxian Cai
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaohong Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chaoshuang Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaoqiong Shao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yujuan Guan
- Eighth People’s Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Hong Deng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Min Wei
- Zhongshan Second People’s Hospital, Zhongshan, Guangdong, China
| | | | - Zefang Ren
- Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Ling Lu
- Laboratory for Hepatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yongyu Mei
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Min Xu
- Eighth People’s Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Jianyun Zhu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Haiyan Shi
- Eighth People’s Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Guoli Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Ying Liu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Fengyu Hu
- Eighth People’s Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Qiumin Luo
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yun Lan
- Eighth People’s Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Fengxia Guo
- Eighth People’s Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Zhixin Zhao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- * E-mail:
| | - Zhiliang Gao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China
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Musser JMB, Heatley JJ, Koinis AV, Suchodolski PF, Guo J, Escandon P, Tizard IR. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture. PLoS One 2015. [PMID: 26222794 PMCID: PMC4519282 DOI: 10.1371/journal.pone.0134080] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture.
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Affiliation(s)
- Jeffrey M. B. Musser
- Schubot Exotic Bird Health Center, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
- * E-mail:
| | - J. Jill Heatley
- Schubot Exotic Bird Health Center, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
- Zoological Medicine, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
| | - Anastasia V. Koinis
- Morris Animal Foundation Veterinary Student Scholar, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
| | - Paulette F. Suchodolski
- Schubot Exotic Bird Health Center, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
| | - Jianhua Guo
- Schubot Exotic Bird Health Center, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
| | - Paulina Escandon
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
| | - Ian R. Tizard
- Schubot Exotic Bird Health Center, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America
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Papastergiou V, Karatapanis S. Current status and emerging challenges in the treatment of hepatitis C virus genotypes 4 to 6. World J Clin Cases 2015; 3:210-20. [PMID: 25789294 PMCID: PMC4360493 DOI: 10.12998/wjcc.v3.i3.210] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/01/2014] [Accepted: 12/29/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) genotypes 4, 5 and 6 are mainly present in Africa, the Middle East and Asia and they have been less extensively studied with respect to epidemiology, natural disease history and therapeutic endpoints. Response rates to a 48-wk combined peginterferon/ribavirin treatment range to 40%-69% for HCV 4, 55%-60% for HCV 5 and 60%-90% for HCV 6. Response-guided schedules are recommended to optimize the outcomes of peginterferon/ribavirin treatment in HCV 4 and, in form of preliminary data, for HCV 6, but no data are yet available to support such an individualization of therapy for HCV 5. Recently, the direct-acting antivirals (DAAs) with pan-genotypic activities simeprevir, sofosbuvir and daclatasvir have been recommended in triple regimens with peginterferon/ribavirin for the treatment of HCV genotypes 4 to 6 infections. In the future, DAA-based interferon-free therapies are awaited to drastically improve treatment outcomes in HCV. However, efforts to improve treatment outcomes with peginterferon/ribavirin should continue, as the HCV 4-6 infected population is mainly based in resource-limited settings with restricted access to the costly DAAs.
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6
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Nguyen NH, McCormack SA, Vutien P, Yee BE, Devaki P, Jencks D, Nguyen MH. Meta-analysis: superior treatment response in Asian patients with hepatitis C virus genotype 6 versus genotype 1 with pegylated interferon and ribavirin. Intervirology 2015; 58:27-34. [PMID: 25592813 PMCID: PMC4351719 DOI: 10.1159/000369097] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 10/09/2014] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Our goal was to systematically and quantitatively assess treatment response between Asian patients with hepatitis C virus genotype 6 (HCV-6) and hepatitis C virus genotype 1 (HCV-1) treated for 48 weeks with pegylated interferon and ribavirin. METHODS We performed a literature search in MEDLINE and EMBASE for 'genotype 6' in August 2013. Additional abstracts from major international scientific conferences from 2012 to 2013 were reviewed. Studies included were original articles with ≥10 treatment-naïve Asian HCV-6 patients. Exclusion criteria were coinfections with hepatitis B virus, HIV and/or other liver diseases. Heterogeneity was defined as a Cochrane Q test with a p value of 0.10 and an I(2) statistic of >50%. RESULTS of a random-effects model are reported. RESULTS A total of 1,046 (503 HCV-6; 543 HCV-1) patients from 12 studies were included in the analysis. The pooled sustained virologic response (SVR) rate was 80.2% (95% CI 74.3-85.0, Q statistic = 20.87, p < 0.035; I(2) = 47.3%) for HCV-6 and 62.5% (95% CI 41.9-79.4, Q statistic = 52.41, p < 0.001; I(2) = 92.37) for HCV-1 patients. HCV-6 patients had a significantly higher SVR rate compared to HCV-1 patients (odds ratio 2.73, 95% CI 1.69-4.41, p < 0.001). Approximately one fourth of patients without early virologic response (EVR) achieved SVR, regardless of genotype (HCV-1, n = 6/23; HCV-6, n = 4/21). CONCLUSIONS Asian patients with HCV-6 can expect higher SVR rates (∼80%) than HCV-1 patients (∼63%). EVR as a stopping rule is less clear in Asian patients with HCV-6 and HCV-1.
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Affiliation(s)
- Nghia H. Nguyen
- School of Medicine at the University of California, San Diego, CA
| | | | - Philip Vutien
- Department of Medicine, Rush University Medical Center, Chicago, IL
| | - Brittany E. Yee
- School of Medicine at the University of California, San Diego, CA
| | - Pardha Devaki
- Department of Medicine, Detroit Medical Center/Wayne State University, Detroit, MI
| | - David Jencks
- Department of Medicine, Stanford University, Palo Alto, CA
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA
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7
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Meta-analysis of patients with hepatitis C virus genotype 6: 48 weeks with pegylated interferon and ribavirin is superior to 24 weeks. Hepatol Int 2014. [PMID: 26202759 DOI: 10.1007/s12072-014-9570-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis C virus genotype 6 (HCV-6) is common in patients from Southeast Asia and the surrounding regions. Optimal treatment duration for HCV-6 is unknown given the inconclusive evidence from studies with varying methodologies and small sample sizes. METHODS A literature search for 'genotype 6' in MEDLINE and EMBASE in October 2013 produced 161 and 251 articles, respectively. Additional abstracts were identified from four major international GI/liver conferences in 2012/2013. Inclusion criteria were original studies with ≥10 HCV-6 treatment-naïve patients treated with pegylated interferon + ribavirin (PEG IFN+RBV). Exclusion criteria were coinfections with HBV, HIV, other HCV genotypes, and/or other liver diseases. Primary outcome was pooled sustained virologic response (SVR). Heterogeneity was defined by Cochrane Q test (p value of 0.10) and I (2) statistic (≥50 %). RESULTS A total of 13 studies with 641 patients were included. The pooled SVR estimate was 77 % (CI 70-83 %) (Q value = 38.4, p value <0.001, I (2) = 68.7 %) overall, 79 % (CI 73-84 %) for the 48-week group and 59 % (CI 46-70 %) for 24-week group, respectively. In studies with direct comparison of the two groups, SVR was superior in patients treated for 48 versus 24 weeks, OR 1.9 (CI 1.08-3.2, p = 0.026). In studies with direct comparison of patients with rapid virologic response (RVR), there was no difference in SVR between 48 versus 24 weeks, OR 1.74 (CI 0.65-4.64, p = 0.27). CONCLUSION Hepatitis C virus genotype 6 patients should be treated for 48 weeks, and those who achieve RVR may receive the shorter 24-week treatment duration. The high SVR (~80 %) with 48 weeks of PEG IFN+RBV therapy may be a cost-effective option for HCV-6 patients from resource-poor regions.
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Increased prevalence of hepatitis C virus subtype 6a in China: a comparison between 2004-2007 and 2008-2011. Arch Virol 2014; 159:3231-7. [PMID: 25085624 PMCID: PMC4221604 DOI: 10.1007/s00705-014-2185-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Accepted: 07/16/2014] [Indexed: 02/07/2023]
Abstract
Different hepatitis C virus (HCV) genotypes exhibit differences in disease pathogenesis and progression, as well as disease outcomes and response to therapy. Tracking the change of HCV genotypes in various epidemiological settings is critical for both disease surveillance and the development of improved antiviral treatment. Here, we tracked the changes in the prevalence of the HCV genotypes in China between 2004-2007 and 2008-2011. HCV-RNA-positive sera were collected from volunteer blood donors during the period 2008-2011. The genotypes were determined by phylogenic analysis using the NS5B and E1 sequences. Geographical and demographic distribution patterns related to the HCV genotypes obtained in 2008-2011 were compared with our previous study, which recorded data in the period 2004-2007. Pearson chi-square test and t-test were used to statistically analyze the results. In 2008-2011, HCV subtypes 1b and 6a were detected in 43.8 % (184/420) and 34.3 % (144/420), respectively. The male/female ratio was found to be higher for HCV genotype 6 than for genotypes 1 and 2. When compared with the period of 2004-2007, although no significant difference was found in gender or age for genotypes 1, 2, 3 and 6, the subtype 6a frequency was significantly increased from 11 % to 26.5 % in the blood donors from outside of Guangdong Province in 2008-2011. A pattern of increase in HCV subtype 6a was found in blood donors outside of Guangdong Province, indicating that HCV subtype 6a has rapidly spread from Guangdong to other regions of China over the past 10 years.
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9
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El-Shamy A, Hotta H. Impact of hepatitis C virus heterogeneity on interferon sensitivity: an overview. World J Gastroenterol 2014; 20:7555-69. [PMID: 24976696 PMCID: PMC4069287 DOI: 10.3748/wjg.v20.i24.7555] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/18/2014] [Accepted: 04/21/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.
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10
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Thong VD, Akkarathamrongsin S, Poovorawan K, Tangkijvanich P, Poovorawan Y. Hepatitis C virus genotype 6: virology, epidemiology, genetic variation and clinical implication. World J Gastroenterol 2014; 20:2927-2940. [PMID: 24659883 PMCID: PMC3961978 DOI: 10.3748/wjg.v20.i11.2927] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 01/06/2014] [Accepted: 01/19/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a serious public health problem affecting 170 million carriers worldwide. It is a leading cause of chronic hepatitis, cirrhosis, and liver cancer and is the primary cause for liver transplantation worldwide. HCV genotype 6 (HCV-6) is restricted to South China, South-East Asia, and it is also occasionally found in migrant patients from endemic countries. HCV-6 has considerable genetic diversity with 23 subtypes (a to w). Although direct sequencing followed by phylogenetic analysis is the gold standard for HCV-6 genotyping and subtyping, there are also now rapid genotyping tests available such as the reverse hybridization line probe assay (INNO-LiPA II; Innogenetics, Zwijnaarde, Belgium). HCV-6 patients present with similar clinical manifestations as patients infected with other genotypes. Based on current evidence, the optimal treatment duration of HCV-6 with pegylated interferon/ribavirin should be 48 wk, although a shortened treatment duration of 24 wk could be sufficient in patients with low pretreatment viral load who achieve rapid virological response. In addition, the development of direct-acting antiviral agents is ongoing, and they give high response rate when combined with standard therapy. Herein, we review the epidemiology, classification, diagnosis and treatment as it pertain to HCV-6.
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Epidemiology and treatment of hepatitis C genotypes 5 and 6. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2014; 27:e8-12. [PMID: 23378985 DOI: 10.1155/2013/624986] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Chronic hepatitis C infection is a major global health problem. The WHO estimates the number of infected people worldwide to be approximately 170 million. The estimated number of hepatitis C virus (HCV)-infected people in Canada is approximately 250,000, with approximately 5000 Canadians newly infected each year. Based on the identification of genomic differences, HCV has been classified into six genotypes; genotype may influence the outcome of antiviral therapy. HCV genotypes 1, 2 and 3 are widely distributed throughout the world and have been the focus of the majority of epidemiological, natural course and treatment studies. Although HCV genotypes 5 and 6 are prevalent in certain geographical areas, they are studied less extensively. HCV genotypes 5 and 6 are uncommon in Canada and account for less than 5% of HCV-infected Canadians. However, immigration and travel can alter the epidemiology of these uncommon genotypes. The present article reviews and summarizes the available data regarding the epidemiology and treatment of HCV genotypes 5 and 6. Genotype 5 is endemic in the northern part of South Africa while genotype 6 is reported primarily in Asia. Available data show that 48 weeks of treatment with a combination of pegylated interferon and ribavirin lead to a higher sustained virological response compared with HCV genotypes 1 and 4. None of the approved direct-acting antiviral agents is currently recommended for the treatment of HCV genotypes 5 or 6.
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Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014; 39:137-47. [PMID: 24251930 DOI: 10.1111/apt.12551] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 06/23/2013] [Accepted: 10/27/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND The global burden of hepatitis C (HCV) infection is mostly found in Africa, the Middle East and Asia, where HCV genotypes 4, 5 and 6 are common. The literature on these genotypes is sparse and this synopsis will review characteristics of patients infected with these genotypes. AIM To review characteristics of patients infected with HCV genotypes 4, 5 and 6. METHODS PubMed search for 'hepatitis C' AND 'genotype 4', 'hepatitis C' AND 'genotype 5', and 'hepatitis C' AND 'genotype 6' was conducted and relevant articles were reviewed. RESULTS Intravenous drug use is generally responsible for HCV genotype 4 infection in developed countries, but unsafe medical practices cause most cases of HCV genotypes 4, 5 and 6 in endemic countries. The sustained virological response (SVR) rate for patients with HCV genotype 4 who receive pegylated interferon and ribavirin for 48 weeks ranges from 40% to 70% in various small studies. The SVR rate is in the 60-70% range for HCV genotype 5 and 70-80% range for HCV genotype 6 following 48 weeks with pegylated interferon and ribavirin. Preliminary data suggest that a shorter course of 24 weeks of pegylated interferon and ribavirin may be acceptable for HCV genotype 6, with an SVR rate of approximately 70%. CONCLUSIONS The current standard-of-care therapy for HCV genotypes 4, 5 and 6 is pegylated interferon and ribavirin for 48 weeks. A shorter course with 24 weeks of therapy may be considered for patients with genotype 6. Newer and much more effective therapies may be forthcoming in the next few years.
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Affiliation(s)
- J M Wantuck
- Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA
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13
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Khaliq S, Latief N, Jahan S. Role of different regions of the hepatitis C virus genome in the therapeutic response to interferon-based treatment. Arch Virol 2013; 159:1-15. [PMID: 23851652 DOI: 10.1007/s00705-013-1780-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 05/28/2013] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) is considered a significant risk factor in HCV-induced liver diseases and development of hepatocellular carcinoma (HCC). Nucleotide substitutions in the viral genome result in its diversification into quasispecies, subtypes and distinct genotypes. Different genotypes vary in their infectivity and immune response due to these nucleotide/amino acid variations. The current combination treatment for HCV infection is pegylated interferon α (PEG-IFN-α) with ribavirin, with a highly variable response rate mainly depending upon the HCV genotype. Genotypes 2 and 3 are found to respond better than genotypes 1 and 4, which are more resistant to IFN-based therapies. Different studies have been conducted worldwide to explore the basis of this difference in therapy response, which identified some putative regions in the HCV genome, especially in Core and NS5a, and to some extent in the E2 region, containing specific sequences in different genotypes that act differently with respect to the IFN response. In the review, we try to summarize the role of HCV proteins and their nucleotide sequences in association with treatment outcome in IFN-based therapy.
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Affiliation(s)
- Saba Khaliq
- Department of Immunology, University of Health Sciences, Lahore, Pakistan,
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14
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Hepatitis C Virus Subtype 6a Infection in an Iranian Patient: A Case Report. Jundishapur J Microbiol 2013. [DOI: 10.5812/jjm.6560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
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Rong X, Lu L, Wang J, Xiong H, Huang J, Chen J, Huang K, Xu R, Wang M, Zhang X, Guo T, Liu Y, Gao G, Fu Y, Nelson KE. Correlation of viral loads with HCV genotypes: higher levels of virus were revealed among blood donors infected with 6a strains. PLoS One 2012; 7:e52467. [PMID: 23285053 PMCID: PMC3524124 DOI: 10.1371/journal.pone.0052467] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 11/13/2012] [Indexed: 12/18/2022] Open
Abstract
Background Both HCV genotypes and viral loads are predictors of therapeutic outcomes among patients treated with α-interferon plus ribavirin; however, such correlation has only been studied for genotypes 1, 2, and 3 but not for genotype 6. Methodology/Findings 299 voluntary blood donors were recruited who were HCV viremic. Their mean age was 31.8; the male/female ratio was 3.82 (225/59). The viral loads of HCV were measured using the COBAS AmpliPrep/COBAS TaqMan test (CAP/CTM) while HCV genotypes were determined by direct sequencing the partial NS5B region. HCV genotypes 1, 2, 3, and 6 were determined in 48.9%, 8.7%, 12.3%, and 30.1% of the donors, respectively, and the levels of mean viral loads in genotype 1 and 6 significantly higher than that of 2 and 3 (P<0.001). As a whole, the viral loads in male donors were higher than in female (P = 0.006). Moreover, the donors' gender and HCV genotypes are independently correlated with the measured viral loads. Conclusion HCV genotype 1 and 6 had significantly higher viral loads than genotype 2 and 3.
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Affiliation(s)
- Xia Rong
- Department of Biochemistry, Medical College of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangzhou Blood Center, Guangzhou, Guangdong, China
| | - Ling Lu
- Center for Viral Oncology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Junzhi Wang
- National Institutes for Food and Drug Control, Beijing, China
| | | | | | - Jinyan Chen
- Guangzhou Blood Center, Guangzhou, Guangdong, China
| | - Ke Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
| | - Ru Xu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
| | - Min Wang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
| | - Xuemei Zhang
- Department of Biochemistry, Medical College of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tai Guo
- National Institutes for Food and Drug Control, Beijing, China
| | - Yueyue Liu
- National Institutes for Food and Drug Control, Beijing, China
| | - Guoquan Gao
- Department of Biochemistry, Medical College of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yongshui Fu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- * E-mail:
| | - Kenrad E. Nelson
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
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16
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Tangkijvanich P, Komolmit P, Mahachai V, Poovorawan K, Akkarathamrongsin S, Poovorawan Y. Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study. J Viral Hepat 2012; 19:423-430. [PMID: 22571904 DOI: 10.1111/j.1365-2893.2011.01566.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The optimal duration of treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) in patients with hepatitis C virus (HCV) genotype 6 is unknown. This study was aimed at determining treatment response on the basis of rapid virological response (RVR) of HCV genotype 6 in comparison with genotypes 1 and 3. Sixty-six treatment naïve patients were treated with PEG-IFN-α2a (180 μg/week) plus weight-based RBV (1000-1200 mg/day). Patients with genotype 1 n = 16) and genotype 3 (n = 16) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients with genotype 6 (n = 34) who achieved RVR were treated for 24 weeks (response-guided therapy) and the remaining patients were treated for 48 weeks (standard therapy). The mean baseline HCV RNA levels were not statistically different between groups (6.4 ± 0.8, 6.0 ± 1.0 and 6.5 ± 0.8 Log(10) IU/mL for genotypes 1, 3 and 6, respectively). Patients with genotypes 1, 3 and 6 achieved RVR in 43.8%, 87.5% and 73.5% of cases, respectively. One patient with genotype 1 and 3 with genotype 6 were considered nonresponders and discontinued therapy. Sustained virological response (SVR) was achieved in 62.5%, 81.3% and 76.5% of patients with genotypes 1, 3 and 6, respectively. The SVR rate in patients with genotype 6 who underwent response-guided therapy was 88%. This pilot study suggested that the SVR rate of HCV genotype 6 was at an intermediate level between those of genotypes 3 and 1. Treatment with PEG-IFN plus RBV for 24 weeks may be sufficient for patients with genotype 6 who achieve RVR. Prospective randomized trials are required to evaluate this response-guided strategy in a larger number of patients with genotype 6.
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Affiliation(s)
- P Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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17
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Thu Thuy PT, Bunchorntavakul C, Tan Dat H, Rajender Reddy K. A randomized trial of 48 versus 24 weeks of combination pegylated interferon and ribavirin therapy in genotype 6 chronic hepatitis C. J Hepatol 2012; 56:1012-1018. [PMID: 22266603 DOI: 10.1016/j.jhep.2011.12.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 10/28/2011] [Accepted: 12/14/2011] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Genotype 6 chronic hepatitis C (HCV) is encountered predominantly in Southeast Asia and data on optimal treatment strategy is limited. This study was aimed at assessing the rate and predictors of sustained virological response (SVR) in genotype 6 chronic HCV following 48 and 24 weeks of pegylated interferon and ribavirin therapy. METHODS This investigator-initiated, open-label randomized trial was conducted in Vietnam between 2008 and 2010. One hundred and five treatment-naïve HCV genotype 6 patients were randomized to either 48-week (N=70) or 24-week (N=35) duration of pegylated interferon (PEG-IFN) alfa-2a 180 mcg/week and ribavirin (RBV) 15mg/kg/day; 92 patients completed the study (63 in the 48-week and 29 in the 24-week group, respectively). Primary outcome was sustained virological response (SVR) as intention-to-treat analysis. RESULTS There was no statistical difference in SVR between 48-week and 24-week treated groups (71% vs. 60%, respectively; p=0.24). In the 48-week and 24-week treatment groups, 81% and 80% of cases achieved rapid virological response (RVR) (p=0.86), and 86% and 80% achieved complete early virological response (p=0.45). Among those patients with RVR, SVR was in 86% (48-weeks), and 75% (24-weeks) of cases, whereas following non-RVR, only 8% of cases had an SVR with 48-week treatment duration. CONCLUSIONS Overall, RVR was achieved in the majority of genotype 6 patients and, in those patients, similar and high rates of SVR were noted following 24-week and 48-week therapy. This observation, however, needs validation in a larger study to demonstrate non-inferiority of the shorter duration therapy. In non-RVR patients, even 48-week therapy achieved low SVR rates.
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Affiliation(s)
| | - Chalermrat Bunchorntavakul
- Rajavithi Hospital, Ministry of Public Health, Bangkok, Thailand; Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Ho Tan Dat
- Medic Medical Center, Ho Chi Minh City, Viet Nam
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA.
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Zhou XM, Chan PKS, Tam JS. Mutations around interferon sensitivity-determining region: A pilot resistance report of hepatitis C virus 1b in a Hong Kong population. World J Gastroenterol 2011; 17:5317-23. [PMID: 22219602 PMCID: PMC3247697 DOI: 10.3748/wjg.v17.i48.5317] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 10/28/2011] [Accepted: 11/05/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore mutations around the interferon sensitivity-determining region (ISDR) which are associated with the resistance of hepatitis C virus 1b (HCV-1b) to interferon-α treatment.
METHODS: Thirty-seven HCV-1b samples were obtained from Hong Kong patients who had completed the combined interferon-α/ribavirin treatment for more than one year with available response data. Nineteen of them were sustained virological responders, while 18 were non-responders. The amino acid sequences of the extended ISDR (eISDR) covering 64 amino acids upstream and 67 amino acids downstream from the previously reported ISDR were analyzed.
RESULTS: One amino acid variation (I2268V, P = 0.023) was significantly correlated with treatment outcome in this pilot study with a limited number of patients, while two amino acid variations (R2260H, P = 0.05 and S2278T, P = 0.05) were weakly associated with treatment outcome. The extent of amino acid variations within the ISDR or eISDR was not correlated with treatment outcome as previously reported.
CONCLUSION: Three amino acid mutations near but outside of ISDR may associate with interferon treatment resistance of HCV-1b patients in Hong Kong.
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19
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Zhou YQ, Wang XH, Hong GH, Zhu Y, Zhang XQ, Hu YJ, Mao Q. Twenty-four weeks of pegylated interferon plus ribavirin effectively treat patients with HCV genotype 6a. J Viral Hepat 2011; 18:595-600. [PMID: 21105968 DOI: 10.1111/j.1365-2893.2010.01373.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The optimal duration of treatment and expected response rate for hepatitis C virus genotype (HCV-6)-infected patients have not been determined. Our aims were to determine the treatment outcome with pegylated interferon (PEG-IFN) plus ribavirin for HCV-6a-infected patients at Southwest Hospital and assess the association of the on-treatment virological response with the sustained virological response (SVR). Medical records were reviewed retrospectively. Twenty-two HCV-6a-infected patients were treated for 24 weeks, and 21 (95.5%) achieved an early virological response (EVR), 20 (90.9%) an end-of-treatment response (ETR) and 18 (81.8%) a SVR. However, only 18 of the 22 HCV-6a-infected patients were tested for serum HCV RNA level at week 4 of treatment and 15 (83.3%) achieved a rapid virological response (RVR). The rates of SVR, RVR, EVR and ETR in these patients were all similar to those in HCV-2/3 treated for 24 weeks and higher than those in HCV-1b-infected patients treated for 48 weeks. A lower relapse rate (10.0%) was seen in HCV-6a compared with HCV-2/3 (12.5%) or HCV-1b-infected patients (23.3%). The positive predictive values of RVR and EVR for HCV-6a were comparable with those for HCV-2/3-infected patients (86.7%vs 90.9%, P = 0.683 and 85.7%vs 86.8%, P = 0.904, respectively). Of the 3 HCV-6a-infected patients who did not achieve a RVR, 2 achieved an EVR and went on to achieve a SVR. The patient who did not achieve an EVR did not achieve a SVR. In summary, our results indicate that 24 weeks of PEG-IFN plus ribavirin can effectively treat patients with HCV-6a chronic infection.
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Affiliation(s)
- Y Q Zhou
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University of Chinese People's Liberation Army, Chongqing, China
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20
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Chao DT, Abe K, Nguyen MH. Systematic review: epidemiology of hepatitis C genotype 6 and its management. Aliment Pharmacol Ther 2011; 34:286-96. [PMID: 21623850 DOI: 10.1111/j.1365-2036.2011.04714.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotype 6 is common among patients from Southeast Asia and the surrounding regions, where HCV prevalence is also high. HCV genotype 6 has great genetic diversity and different response to antiviral therapy compared with the more commonly known genotype 1. AIM Our goal was to provide a systematic review of the current literature on the epidemiology, classification and treatment of HCV genotype 6. METHODS A search using PubMed for 'hepatitis C' AND 'genotype 6' produced a total of 47 articles, of which 33 articles were found to be relevant and included in this review. Additional articles were identified using the reference lists of these 33 primary articles. RESULTS The prevalence of HCV genotype 6 is estimated to be as high as 50% in some regions of Southeast Asia with demonstrated significance among intravenous drug users and thalassemia major patients. Although previous line probe assays may have misclassified HCV genotype 6 as genotype 1, newer line probe assays can more accurately and reliably determine HCV genotype. Patients infected with HCV genotype 6 respond better to interferon-based therapy compared with those infected with genotype 1, although patient baseline clinical characteristics and side effect profiles are similar between HCV genotype 6 and other HCV genotypes. CONCLUSIONS Future studies should seek to clarify issues regarding early predictors for treatment response in patients with HCV genotype 6, and the impact of ethnic and genotypic factors to treatment response in HCV genotype 6 patients.
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Affiliation(s)
- D T Chao
- College of Human Medicine, Michigan State University, East Lansing, MI, USA
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21
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Lam KD, Trinh HN, Do ST, Nguyen TT, Garcia RT, Nguyen T, Phan QQ, Nguyen HA, Nguyen KK, Nguyen LH, Nguyen MH. Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatment-naive chronic hepatitis C genotype 6. Hepatology 2010; 52:1573-80. [PMID: 21038410 DOI: 10.1002/hep.23889] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open-label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN-α2a 180 μg subcutaneously weekly and weight-based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention-to-treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.3 ± 1.1 IU/mL) were enrolled: 27 patients to 24 weeks and 33 patients to 48 weeks of therapy. In the 24-week and 48-week groups, 96% and 97% achieved early virologic response (P = 0.90); 89% versus 94% achieved end of therapy virologic response (P = 0.48). SVR was achieved in 70% versus 79% of patients assigned to 24 weeks versus 48 weeks (P = 0.45). Rapid virologic response (RVR) was a significant predictor of SVR in the 48-week group and trending towards significance in the 24-week group: 82% and 83% of those with RVR achieved SVR versus 33% and 29% for the 24-week and 48-week groups, respectively (P = 0.07 and P = 0.02). CONCLUSION There was no significant difference in SVR rates in patients with HCV genotype 6 treated with PEG IFN-α2a and RBV for 24 versus 48 weeks.
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Affiliation(s)
- Khoa D Lam
- Pacific Health Foundation, San Jose, CA, USA
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22
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Nguyen NH, VuTien P, Garcia RT, Trinh H, Nguyen H, Nguyen K, Levitt B, Nguyen MH. Response to pegylated interferon and ribavirin in Asian American patients with chronic hepatitis C genotypes 1 vs 2/3 vs 6. J Viral Hepat 2010; 17:691-7. [PMID: 20002562 DOI: 10.1111/j.1365-2893.2009.01226.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Chronic hepatitis C is generally underappreciated in Asian Americans, and most pivotal studies were conducted in western countries and only included a small numbers of Asian patients. Our goal was to examine and compare treatment outcomes in these patients with genotypes 1 vs 2/3 vs 6. We performed a retrospective cohort study of 167 consecutive treatment-naïve Asian American patients treated with pegylated interferon (PEG IFN) plus ribavirin (RBV) at two community clinics in Northern California from 12/00 to 1/08. Primary outcome was sustained virological response rate by intention-to-treat analysis. The overall completion rate was 76%, and treatment adherence (completion of ≥ 75-80% PEG IFN + RBV dose for ≥ 75-80% of intended duration) was 74%. Significant depression was noted in only 4% of patients. Sustained virologic response in patients with genotype 6 treated for 48 weeks was similar to that seen in those with genotype 2/3 (74%vs 75%, P = 0.89) and significantly higher than those with genotype 1 (74%vs 49%, P = 0.016). On multivariate analysis inclusive of sex, age, body mass index (≤ 25 vs > 25) and viral load, only treatment adherence and genotype (2/3 and 6 treated for 48 weeks) were found to be significant predictors of sustained virologic response. We conclude that significant depression is rare in Asian American patients (4%). Patients with genotype 6 treated for 48 weeks appear to have a similar treatment response rate as patients with genotype 2/3 and a significantly higher response rate than those with genotype 1.
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Affiliation(s)
- N H Nguyen
- Pacific Health Foundation, San Jose, CA, USA
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Zhou DXM, Chan PKS, Zhang T, Tully DC, Tam JS. Sequence diversity of hepatitis C virus 6a within the extended interferon sensitivity-determining region correlates with interferon-alpha/ribavirin treatment outcomes. Virus Res 2010; 153:44-9. [PMID: 20624431 DOI: 10.1016/j.virusres.2010.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Revised: 07/01/2010] [Accepted: 07/02/2010] [Indexed: 12/13/2022]
Abstract
Studies on the association between sequence variability of the interferon sensitivity-determining region (ISDR) of hepatitis C virus and the outcome of treatment have reached conflicting results. In this study, 25 patients infected with HCV 6a who had received interferon-alpha/ribavirin combination treatment were analyzed for the sequence variations. 14 of them had the full genome sequences obtained from a previous study, whereas the other 11 samples were sequenced for the extended ISDR (eISDR). This eISDR fragment covers 192 bp (64 amino acids) upstream and 201 bp (67 amino acids) downstream from the ISDR previously defined for HCV 1b. The comparison between interferon-alpha resistance and response groups for the amino acid mutations located in the full genome (6 and 8 patients respectively) as well as the mutations located in the eISDR (10 and 15 patients respectively) showed that the mutations I2160V, I2256V, V2292I (P<0.05) within eISDR were significantly associated with resistance to treatment. However, the extent of amino acid variations within previously defined ISDR was not associated with resistance to treatment as previously reported. Four amino acid variations I248V (P=0.03-0.06) within E1, R445K (P=0.02-0.05) and S747T (P=0.03) within E2, I861V (P=0.01) within NS2 which located outside the eISDR may also associate with treatment outcome as identified by a prescreening of variations within 14 HCV 6a full genomes.
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Affiliation(s)
- Daniel X M Zhou
- Fudan University, Shanghai Public Health Clinical Center, China.
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Similar treatment response to peginterferon and ribavirin in Asian and Caucasian patients with chronic hepatitis C. Am J Gastroenterol 2010; 105:1110-5. [PMID: 19904247 DOI: 10.1038/ajg.2009.635] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Previous studies have found ethnicity to be an important predictor of outcomes of treatment with peginterferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C. Although the expected sustained virological response (SVR) rates of Hispanics and African Americans are lower than those of Caucasians, SVR rates in Asians appear to be more favorable. However, in some of these studies, hepatitis C virus (HCV) genotype was identified by INNO-LiPA assay, which can mistype the easier-to-treat HCV genotype 6 as genotype 1. Our goal was to compare SVR rates among Caucasian and Asian-American patients with genotype 1 and 2/3 infection whose HCV genotypes were accurately classified by core sequencing testing. METHODS A cohort of 269 consecutive treatment-naive HCV-infected patients with genotype 1 or 2/3 (157 Caucasians and 112 Asians) treated with PEG-IFN+RBV from January 2001 to November 2007 at four community-based gastroenterology clinics in Northern California were studied. The analysis of data was by intention-to-treat. RESULTS The SVR rates for patients with genotype 1 were 45% for Caucasians and 52% for Asians (P=0.37). The SVR rates for patients with genotype 2/3 infection was 77% for Asians and 74% for Caucasians (P=0.7). On multivariate logistic regression analyses adjusting for age, alanine aminotransferase (ALT), baseline viral load, HCV genotype, and treatment adherence, we did not find Asian ethnicity to predict SVR. On a separate analysis, we found that Asians who had HCV genotype 1 or 1b by the less accurate INNO-LiPA assay had significantly higher SVR rates than Caucasians with genotype 1 (64% vs. 45%, respectively, P=0.03). CONCLUSIONS SVR rates were similar in Asian Americans and Caucasians infected with HCV genotype 1 or 2/3 when HCV genotype classification was accurately determined.
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Risk factors, genotype 6 prevalence, and clinical characteristics of chronic hepatitis C in Southeast Asian Americans. Hepatol Int 2010; 4:523-9. [PMID: 20827411 DOI: 10.1007/s12072-010-9181-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2009] [Accepted: 03/13/2010] [Indexed: 12/18/2022]
Abstract
PURPOSE Although infection with hepatitis C virus (HCV) affects 32 million individuals from Southeast Asia, little is known about the mode of HCV acquisition and the epidemiology of chronic hepatitis C (CHC) in these individuals. Our goal was to examine risk factors for HCV acquisition, prevalence, and clinical characteristics of HCV genotype 6 compared with genotypes 1 and 2/3 in Southeast Asian (SEA) patients. METHODS We performed a cross-sectional study of 308 consecutive SEA Americans with CHC evaluated by five gastroenterologists from January 2000 to December 2008 at two community clinics in northern California via medical record review, using a case report form. RESULTS A significant proportion of patients (41%) could not recall any specific risk factors for HCV acquisition. The most commonly reported risk factor in patients who reported at least one risk factor was history of surgeries (34%), followed by blood transfusion (25%) and acupuncture (13%). Among patients with core sequence testing for HCV genotype (n = 181), the most common HCV genotypes were genotype 1 (42%) and genotype 6 (41%), followed by genotype 2/3 (17%). There were no major differences in the clinical and virological characteristics between the different genotype groups (1 vs. 2/3 vs. 6). CONCLUSION HCV genotype 6 is as common as genotype 1 in SEAs. Commonly known risk factors for HCV acquisition were not readily identifiable in a large proportion of SEA Americans (41%) and may not be useful in identifying at-risk individuals for HCV screening in this population.
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Tsang OTY, Zee JST, Chan JMC, Li RST, Kan YM, Li FTW, Lo FH, Chow DA, Cheung KWL, Chan KH, Yeung YW, Ng FH, Li MKK, Kwan WK, Lai TST. Chronic hepatitis C genotype 6 responds better to pegylated interferon and ribavirin combination therapy than genotype 1. J Gastroenterol Hepatol 2010; 25:766-71. [PMID: 20492332 DOI: 10.1111/j.1440-1746.2009.06163.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Chronic hepatitis C genotype 6 is common in Hong Kong, especially among i.v. drug abusers. Responses of these patients to combination of pegylated interferon and ribavirin treatment were inconsistent and the numbers of patients involved in previous studies were small. We performed a retrospective study to compare the therapeutic responses of this regimen in patients infected with genotype 6 and genotype 1. METHODS Seventy patients with either genotype 6 or genotype 1 were recruited. Both groups received 800-1200 mg of ribavirin daily plus either 180 mg of pegylated alpha-interferon-2a or 1.5 mg/kg pegylated alpha-interferon-2b weekly for 48 weeks. Their responses to treatments were compared. RESULTS The early virological response to combination therapy of patients with genotype 6 was significantly better than that of genotype 1 (88.6% vs 74.3%, P = 0.03). Significant difference was also identified in the end of treatment response of the two genotypes (60% vs 81.4% for genotype 1 and 6, respectively; P = 0.005). The sustained virological response (SVR) to treatment in patients with genotype 6 was also significantly superior to that of patients with genotype 1 (75.7% vs 57.1%, P = 0.02). Multiple logistic regression analysis demonstrated that age of 55 years or less, genotypes of hepatitis C virus, liver biopsy staging and baseline hepatitis C virus RNA of 200,000 IU/mL or less were independent predictors for better SVR in this cohort. CONCLUSION Patients with chronic hepatitis C genotype 6 respond better to pegylated interferon and ribavirin combination treatment than patients with genotype 1.
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Affiliation(s)
- Owen T-Y Tsang
- Department of Medicine and Geriatrics of Princess Margaret Hospital, Hong Kong.
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Antaki N, Craxi A, Kamal S, Moucari R, Van der Merwe S, Haffar S, Gadano A, Zein N, Lai CL, Pawlotsky JM, Heathcote EJ, Dusheiko G, Marcellin P. The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report. Liver Int 2010; 30:342-55. [PMID: 20015149 DOI: 10.1111/j.1478-3231.2009.02188.x] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Abstract Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification. It is also highly prevalent in sub-Saharan Africa and in the Middle East. In Europe, its prevalence has recently increased particularly among intravenous drug users and in immigrants. HCV-5 is mainly found in South Africa, where it represents 40% of all HCV genotypes, but four pockets of HCV-5 were found in France, Spain, Syria and Belgium and sporadic cases were found elsewhere. The mode of transmission is mainly iatrogenic and transfusion. HCV-6 is found in Hong Kong, Vietnam, Thailand and Myanmar and also in American and Australian from Asian origin. The response to treatment in HCV-4 is intermediate between HCV-1 and HCV-2 and HCV-3. A sustained viral response is achieved in 43-70% with pegylated interferon and ribavirin. It is higher in Egyptians than Europeans and Africans and is negatively related to insulin resistance and to the severity of fibrosis. It increases to >80% with 24 weeks of therapy only if a rapid virological response is achieved. In HCV-5, a sustained virological response is achieved in >60% with 48 weeks of therapy. HCV-6 is also considered an easy-to-treat genotype, leading to a response in 60-85% of cases.
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Affiliation(s)
- Nabil Antaki
- Department of Gastroenterology and Hepatology, Saint Louis Hospital, Aleppo, Syria.
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Kobayashi M, Akuta N, Suzuki F, Hosaka T, Sezaki H, Kobayashi M, Suzuki Y, Arase Y, Ikeda K, Watahiki S, Mineta R, Iwasaki S, Miyakawa Y, Kumada H. Influence of amino-acid polymorphism in the core protein on progression of liver disease in patients infected with hepatitis C virus genotype 1b. J Med Virol 2010; 82:41-8. [DOI: 10.1002/jmv.21629] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Abstract
The reader may be eager to examine in which diseases ozonetherapy can be proficiently used and she/he will be amazed by the versatility of this complementary approach (Table 9 1). The fact that the medical applications are numerous exposes the ozonetherapist to medical derision because superficial observers or sarcastic sceptics consider ozonetherapy as the modern panacea. This seems so because ozone, like oxygen, is a molecule able to act simultaneously on several blood components with different functions but, as we shall discuss, ozonetherapy is not a panacea. The ozone messengers ROS and LOPs can act either locally or systemically in practically all cells of an organism. In contrast to the dogma that “ozone is always toxic”, three decades of clinical experience, although mostly acquired in private clinics in millions of patients, have shown that ozone can act as a disinfectant, an oxygen donor, an immunomodulator, a paradoxical inducer of antioxidant enzymes, a metabolic enhancer, an inducer of endothelial nitric oxide synthase and possibly an activator of stem cells with consequent neovascularization and tissue reconstruction.
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Affiliation(s)
- Velio Bocci
- Department of Physiology, University of Siena, via A. Moro 2, 53100 Siena, Italy
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Legrand-Abravanel F, Colson P, Leguillou-Guillemette H, Alric L, Ravaux I, Lunel-Fabiani F, Bouviers-Alias M, Trimoulet P, Chaix ML, Hézode C, Foucher J, Fontaine H, Roque-Afonso AM, Gassin M, Schvoerer E, Gaudy C, Roche B, Doffoël M, D'Alteroche L, Vallet S, Baazia Y, Pozzetto B, Thibault V, Nousbaum JB, Roulot D, Coppere H, Poynard T, Payan C, Izopet J. Influence of the HCV subtype on the virological response to pegylated interferon and ribavirin therapy. J Med Virol 2009; 81:2029-2035. [PMID: 19856464 DOI: 10.1002/jmv.21583] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2025]
Abstract
The hepatitis C virus genotype is considered to be the most important baseline predictor of a sustained virological response in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The influence of the subtype on the sustained virological response was investigated in patients infected with genotypes 1, 4, 5, or 6. This study was done on 597 patients with chronic hepatitis C who were given pegylated interferon and ribavirin for 48 weeks. The overall rate of sustained virological response in the 597 patients was 37.8%. Univariate analysis indicated that the sustained virological response of patients infected with subtype 1b (39%) tended to be higher than that of patients infected with subtype 1a (30.6%; P = 0.06) and it was similar to those patients infected with subtypes 4a (51.3%; P = 0.12) or 4d (51.7%; P = 0.16). Multivariate analysis indicated that five factors were independently associated with sustained virological response: the age (OR 0.97; 95% CI = 0.95-0.99), absence of cirrhosis (OR: 2.92; 95% CI = 1.7-5.0; P < 0.01), absence of HIV co-infection (OR: 2.08; 95% CI = 1.2-3.5; P < 0.01), low baseline plasma HCV RNA concentration (OR: 1.74; 95% CI = 1.2-2.6; P < 0.01), and the subtype 1b (OR: 1.61; 95% CI = 1.0-2.5; P = 0.04) or subtypes 4a and 4d (OR: 2.03; 95% CI = 1.1-3.8; P = 0.03). In conclusion, among difficult-to-treat genotypes, the subtype 1a is associated with a lower response to anti-HCV therapy than subtypes 1b, 4a, and 4d.
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Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Miyakawa Y, Kumada H. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral loads. Dig Dis Sci 2009; 54:1317-24. [PMID: 18958621 DOI: 10.1007/s10620-008-0500-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2008] [Accepted: 08/22/2008] [Indexed: 12/14/2022]
Abstract
BACKGROUND Response to treatment in patients with chronic hepatitis C, with reference to age and gender, has not been examined fully. AIM The influence of gender and age on treatment with pegylated interferon (PEG-IFN) and ribavirin was evaluated in a retrospective study. METHODS PEG-IFN and ribavirin were given for 48 weeks to 179 men and 121 women infected with hepatitis C virus (HCV) of genotype 1b in high viral loads (>100 kIU/ml). RESULTS Sustained virological response at 24 weeks after treatment was poorer in women than men who were aged >or=50 years (22% vs 53%, P < 0.001). Among the patients aged >or=50 years who had received >or=80% of the doses of PEG-IFN, ribavirin, or both, women responded less often than men (26% vs 64%, P < 0.001; 33% vs 61%, P = 0.022; and 32% vs 63%, P = 0.016; respectively). In multivariate analysis, male gender, retention of indocyanine green, ribavirin dose and compliance with therapy increased sustained virological response. CONCLUSIONS Response to combined PEG-IFN and ribavirin is poorer in female than male patients with hepatitis C who are aged >or=50 years, irrespective of compliance with treatment. Low estrogen levels in older women could be responsible for their impaired response to PEG-IFN and ribavirin.
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Affiliation(s)
- Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
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Antaki N, Marcellin P. What is the safe duration of therapy for patients infected with HCV genotype 6? ACTA ACUST UNITED AC 2008; 6:78-9. [DOI: 10.1038/ncpgasthep1335] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Accepted: 11/21/2008] [Indexed: 01/06/2023]
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Fung J, Lai CL, Hung I, Young J, Cheng C, Wong D, Yuen MF. Chronic hepatitis C virus genotype 6 infection: response to pegylated interferon and ribavirin. J Infect Dis 2008; 198:808-12. [PMID: 18657036 DOI: 10.1086/591252] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND To date, no study has evaluated pegylated interferon for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6. We aimed to determine the efficacy of pegylated interferon plus ribavirin for treating infection with genotype 6 versus genotype 1. METHODS Forty-two patients chronically infected with HCV (for genotype 1, n = 21; for genotype 6, n = 21) were treated with pegylated interferon alpha-2a (n = 20) or alpha-2b (n = 22) combined with oral ribavirin for 48 weeks. RESULTS There was no difference between genotypes 1 and 6 in the rates of early virological response (76% vs. 81%; P > .05) and end-of-treatment response (71% vs. 81%; ). Patients infected with genotype 6 had a higher rate of sustained virological response (SVR) than did patients infected with genotype 1 (86% vs. 52%; P = .019). The overall adverse-effects profile was similar in both genotype groups. There was no significant difference in the rate of SVR between patients receiving pegylated interferon alpha-2a and those receiving alpha-2b. Multivariate analysis showed that genotype was the only significant factor associated with SVR (P = .039). CONCLUSIONS Treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. Further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection.
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Affiliation(s)
- James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
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Gottwein JM, Bukh J. Cutting the gordian knot-development and biological relevance of hepatitis C virus cell culture systems. Adv Virus Res 2008; 71:51-133. [PMID: 18585527 DOI: 10.1016/s0065-3527(08)00002-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Worldwide approximately 180 million people are chronically infected with hepatitis C virus (HCV). HCV isolates exhibit extensive genetic heterogeneity and have been grouped in six genotypes and various subtypes. Additionally, several naturally occurring intergenotypic recombinants have been described. Research on the viral life cycle, efficient therapeutics, and a vaccine has been hampered by the absence of suitable cell culture systems. The first system permitting studies of the full viral life cycle was intrahepatic transfection of RNA transcripts of HCV consensus complementary DNA (cDNA) clones into chimpanzees. However, such full-length clones were not infectious in vitro. The development of the replicon system and HCV pseudo-particles allowed in vitro studies of certain aspects of the viral life cycle, RNA replication, and viral entry, respectively. Identification of the genotype 2 isolate JFH1, which for unknown reasons showed an exceptional replication capability and resulted in formation of infectious viral particles in the human hepatoma cell line Huh7, led in 2005 to the development of the first full viral life cycle in vitro systems. JFH1-based systems now enable in vitro studies of the function of viral proteins, their interaction with each other and host proteins, new antivirals, and neutralizing antibodies in the context of the full viral life cycle. However, several challenges remain, including development of cell culture systems for all major HCV genotypes and identification of other susceptible cell lines.
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Affiliation(s)
- Judith M Gottwein
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
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Nguyen MH, Trinh HN, Garcia R, Nguyen G, Lam KD, Keeffe EB. Higher rate of sustained virologic response in chronic hepatitis C genotype 6 treated with 48 weeks versus 24 weeks of peginterferon plus ribavirin. Am J Gastroenterol 2008; 103:1131-5. [PMID: 18477343 DOI: 10.1111/j.1572-0241.2008.01793.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Infection with hepatitis C virus (HCV) genotype 6 is common in patients from parts of China and Southeast Asia. No study to date has examined the treatment response to peginterferon and ribavirin (PEG IFN + RBV) in these patients, or the effects of treatment duration on sustained virologic response (SVR) rates. METHODS We performed a retrospective study of 190 consecutive Asian-American patients who were diagnosed with HCV genotype 6 at a gastroenterology clinic in northern California between 2001 and 2004, 66 of whom were treatment-naïve and subsequently completed 24 wk of IFN + RBV or PEG IFN + RBV or 48 wk of PEG IFN + RBV therapy. The primary outcome was SVR. RESULTS There was no statistical difference in SVR of 31 patients treated with 24 wk of IFN + RBV and in 23 patients treated with 24 wk of PEG IFN + RBV (51.6%vs 39%, P= 0.363). The SVR in 12 patients treated with 48 wk of PEG IFN + RBV was significantly higher than that in those treated for only 24 wk (75%vs 39%, P= 0.044). CONCLUSIONS Treatment-eligible patients with HCV genotype 6 should be treated with a full course of 48 wk as tolerated. Larger prospective studies of patients with HCV genotype 6 are needed to confirm the optimal treatment duration with PEG IFN + RBV.
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Affiliation(s)
- Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
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Khan A, Kurbanov F, Tanaka Y, Elkady A, Sugiyama M, Dustov A, Mizokami M. Epidemiological and clinical evaluation of hepatitis B, hepatitis C, and delta hepatitis viruses in Tajikistan. J Med Virol 2008; 80:268-276. [PMID: 18098133 DOI: 10.1002/jmv.21057] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The implication of genotypes is recognized increasingly in the clinical course of hepatitis B virus (HBV) and in response to anti-viral drugs of hepatitis C virus (HCV). Genotypic prevalence of both etiological agents varies geographically and no data are available for Tajikistan. To investigate the epidemiology and clinical significance of HBV and HCV genotypes in chronic hepatitis (group 1) and liver cirrhosis/hepatocellular carcinoma (HCC) (group 2) patients in Tajikistan, 124 patients with chronic liver disease (group 1 = 84 and group 2 = 40) were enrolled. Genotypes of HBV, HCV, and delta hepatitis virus (HDV) were determined by sequencing. The overall prevalence of anti-HCV, HCV core antigen (HCVcAg) and HBsAg was 46% (57/124) and 41.1% (51/124), respectively. Coinfection of HCV/HBV, HBV/HDV, and HCV/HBV/HDV was found in 4.8% (6/124), 11.2% (12/124), and 0.8% (1/124) of cases, respectively. HDV genotype 1 was found in 19.6% (10/51) of HBsAg-positive patients. The HBV/HDV coinfection was relatively high in group 2 compared to group 1 (15% vs. 7.1%). HCV/1b detected in 84.6% (44/52) of HCV RNA-positive patients, followed by 3a (7.6%), 2a (5.7%), and 2c (1.9%). HBV/D was detected in 94.1% (48/51) of HBsAg-positive patients, followed by HBV/A [5.8% (3/51)]. T1762/A1764 double mutation was associated with liver cirrhosis/HCC in HBV-infected patients (P = 0.0004). This is the first study on the molecular epidemiology of hepatitis viruses among chronic liver diseases patients in Tajikistan. Among HBV-infected patients, the T1762/A1764 mutation was associated with liver cirrhosis/HCC.
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MESH Headings
- Adolescent
- Adult
- Cluster Analysis
- Comorbidity
- DNA, Viral/genetics
- DNA, Viral/isolation & purification
- Female
- Hepacivirus/classification
- Hepacivirus/genetics
- Hepatitis B Surface Antigens/blood
- Hepatitis B virus/classification
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/epidemiology
- Hepatitis B, Chronic/virology
- Hepatitis C Antibodies/blood
- Hepatitis C Antigens/blood
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/virology
- Hepatitis D, Chronic/epidemiology
- Hepatitis D, Chronic/virology
- Hepatitis Delta Virus/classification
- Hepatitis Delta Virus/genetics
- Humans
- Male
- Middle Aged
- Molecular Epidemiology
- Molecular Sequence Data
- Phylogeny
- RNA, Viral/genetics
- RNA, Viral/isolation & purification
- Sequence Analysis, DNA
- Sequence Homology
- Tajikistan/epidemiology
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Affiliation(s)
- Anis Khan
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Japan
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Pegylated Interferons: Clinical Applications in the Management of Hepatitis C Infection. HEPATITIS C VIRUS DISEASE 2008. [PMCID: PMC7122148 DOI: 10.1007/978-0-387-71376-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Nadarajah R, Khan GY, Miller SA, Brooks GF. Evaluation of a new-generation line-probe assay that detects 5' untranslated and core regions to genotype and subtype hepatitis C virus. Am J Clin Pathol 2007; 128:300-4. [PMID: 17638666 DOI: 10.1309/rbaac0hjfwrjb1hd] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The VERSANT HCV Genotype 2.0 Assay (LiPA 2.0; Innogenetics, Ghent, Belgium; distributed by Siemens Medical Solutions Diagnostics, Tarrytown, NY) is a new-generation line-probe assay that simultaneously detects sequences in the 5' untranslated (5'UTR) and core regions to genotype and subtype hepatitis C virus (HCV). We tested 60 specimens of known genotype and subtype and 2 specimens with mixed infections with the LiPA 2.0 assay. After arbitration based on genotype and subtype determined by sequencing, there was concordance in 58 of 60 specimens (specificity, 96.7%). Computer-assisted typing yielded comparable results, but much more rapidly. Of 67 clinical specimens, 64 readily yielded genotype and subtype; 3 indeterminate specimens were typed by sequencing and were uncommon types not in the database. The newgeneration line-probe assay that detects the 5'UTR and core regions to genotype and subtype HCV is applicable to more than 95% of specimens. Interpretation is facilitated by computer-assisted analysis.
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Affiliation(s)
- Rohan Nadarajah
- Microbiology Section, Clinical Laboratories, Department of Laboratory Medicine, University of California San Francisco, CA 94107, USA
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39
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40
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Bonny C, Fontaine H, Poynard T, Hézode C, Larrey D, Marcellin P, Bourlière M, Bronowicki JP, Merle P, Zarski JP, Sapey T, Guillemard C, Ughetto S, Henquell C, Nicolas C, Roche C, Randl K, Bommelaer G, Abergel A. Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study. Aliment Pharmacol Ther 2006; 24:593-600. [PMID: 16907892 DOI: 10.1111/j.1365-2036.2006.03018.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
AIM To assess the rate of sustained virological response in naïve hepatitis C virus-type 5 patients treated by standard interferon or pegylated-interferon [corrected] (peg-interferon) and ribavirin combination for 48 weeks. PATIENTS AND METHODS A total of 87 hepatitis C virus patients were included from 12 centres in France; 28 patients received interferon plus ribavirin and 59 were treated with peg-interferon plus ribavirin. RESULTS Baseline characteristics were: mean age 58 +/- 11 years, sex ratio 1, 66% had metavir fibrosis score >or=F2, 21% were cirrhotics and 53% had pretherapeutic viral load >or=800,000 IU/mL. Sustained virological response was achieved in 64% and 58% of hepatitis C virus-5 patients treated with interferon and peg-interferon, respectively (NS). In adherent patients, sustained virological response was obtained in 75% of patients. Sustained virological response in hepatitis C virus-5 patients (60%) was significantly higher than sustained virological response in hepatitis C virus-1 patients (37%) (P = 0.0499) and not significantly different from sustained virological response in hepatitis C virus-2-3 patients (63%) (P = 0.8098). CONCLUSIONS Combination therapy is effective in 60% of hepatitis C virus-5-infected patients. Sustained virological response seems better in hepatitis C virus-5 patients than in hepatitis C virus-1 patients, and is similar to that of hepatitis C virus-2-3 patients. More studies are needed to determine optimal duration of treatment in hepatitis C virus-5 patients.
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Affiliation(s)
- C Bonny
- Service d'Hépato-Gastroentérologie, Hôtel-Dieu, Clermont-Ferrand, France.
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Boulestin A, Kamar N, Sandres-Sauné K, Legrand-Abravanel F, Alric L, Vinel JP, Rostaing L, Izopet J. Twenty-four hour kinetics of hepatitis C virus and antiviral effect of alpha-interferon. J Med Virol 2006; 78:365-71. [PMID: 16419107 DOI: 10.1002/jmv.20548] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Numerous studies reported that patients infected by the genotype 1 of hepatitis C virus (HCV) and/or with a high baseline viral load responded poorly to antiviral therapy. Study of viral kinetics has provided clues to the understanding of non-response to alpha-interferon (IFN-alpha)-based therapy. The objective of this study was to clarify the influence of viral factors such as the genotype and baseline viral load on HCV resistance to treatment through the study of their impact on the first phase of viral decline. HCV RNA levels were determined frequently following the administration of 3 million units of IFN-alpha in 22 chronic HCV carriers. The evolution of HCV RNA level over 24 hr was different in genotype 1-infected patients, compared to that in patients infected by other genotypes. The viral load decline at 24 hr was lower in patients with genotype 1. Patients with a high baseline viral load exhibited a viral dynamics different from patients with a lower level of viremia; the extent of the first phase was also lower in these patients. Non-responder patients had a slower viral decay on day 1 of therapy than patients who cleared the virus under treatment. In conclusion, 24 hr HCV dynamics is regulated by genotype and baseline viral load. Genotype 1 strains and those that produce high viral loads are the most resistant to the antiviral action of IFN-alpha. Resistant HCV strains could be distinguished from sensitive viruses as early as a few hours after the beginning of the treatment.
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Affiliation(s)
- Anne Boulestin
- Laboratoire de Virologie EA 2046-IFR30, Chu Purpan, Toulouse, France.
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Verbeeck J, Maes P, Lemey P, Pybus OG, Wollants E, Song E, Nevens F, Fevery J, Delport W, Van der Merwe S, Van Ranst M. Investigating the origin and spread of hepatitis C virus genotype 5a. J Virol 2006; 80:4220-6. [PMID: 16611881 PMCID: PMC1472033 DOI: 10.1128/jvi.80.9.4220-4226.2006] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2005] [Accepted: 01/16/2006] [Indexed: 02/07/2023] Open
Abstract
Epidemiological and phylogenetic studies of hepatitis C virus (HCV) have identified six major HCV genotypes and have attempted to characterize their origin and spread worldwide. Putative regions of endemic infection have been identified for all HCV genotypes except HCV genotype 5a. Although HCV genotype 5a was previously thought to be largely restricted to the northern part of South Africa, this study reports an unexpected cluster of the genotype in West Flanders Province in Belgium. To investigate the molecular epidemiology of this cluster and of HCV genotype 5a in general, a rigorous phylogenetic analysis of Belgian and South African HCV genotype 5a samples was performed. Remarkably, the Belgian and South African strains form two distinct clusters of similar diversity. We used a Bayesian coalescent method to estimate the rate of virus spread through time for HCV genotype 5a in both regions. Our results indicate that HCV genotype 5a strains have been spreading independently in Belgium and South Africa for more than 100 years, with a rate of spread characteristic of an epidemic genotype. These findings have major implications for tracing the origin of HCV genotype 5a. Here, we speculate about the possible origins of these clusters.
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Affiliation(s)
- Jannick Verbeeck
- Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium
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Yuen MF, Lai CL. Response to combined interferon and ribavirin is better in patients infected with hepatitis C virus genotype 6 than genotype 1 in Hong Kong. Intervirology 2005; 49:96-8. [PMID: 16166796 DOI: 10.1159/000087270] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Data on the treatment efficacy of interferon (IFN)-alpha and ribavirin in patients with chronic hepatitis infected with hepatitis C virus (HCV) of genotype 6 are lacking. A study has been reported from Hong Kong which compared the treatment efficacy of IFN-alpha and ribavirin in the treatment of chronic HCV infection with genotypes 1 and 6. Twenty-four patients with HCV genotype 1 and 16 patients with HCV genotype 6 were studied. The baseline demographic data including median age, gender ratio, alanine aminotransferase levels, bilirubin levels, HCV RNA levels and histological scores were comparable between the two groups of patients. All patients received IFN-alpha 5 million units three times per week and ribavirin (1,000 mg for those weighing </=75 kg and 1,200 mg for those weighing >75 kg) for 1 year. Patients infected with HCV genotype 6 achieved virological response significantly higher than those with HCV genotype 1 (67 vs. 33% at week 24, p = 0.02; 75 vs. 42% at the end of treatment, p = 0.05; 63 vs. 29% at 6 months after completion of treatment, p = 0.04). Histological improvement in inflammatory activity and fibrosis in the liver were observed in 25% and 25% of patients infected with HCV genotype 6 in contrast to only 13 and 8% in patients infected with HCV genotype 1; however, the differences were not statistically significant. In conclusion, patients with HCV genotype 6 gain a better response to combined treatment with IFN-alpha and ribavirin than those with HCV genotype 1 and achieve a significantly higher rate of sustained virological response.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China.
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Au WY, Lam CCK, Liu CL, Yuen MF. Hepatitis C Virus Infection in Adult Chinese Hemophilia Patients Negative for the Human Immunodeficiency Virus: Treatment Results with Interferon and Ribavirin. Int J Hematol 2005; 82:259-61. [PMID: 16207601 DOI: 10.1532/ijh97.a10417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Hepatitis C virus (HCV) eradication in hemophilia patients depends on viral and patient factors. We report the treatment results with interferon 3 (5 megaunits, 3 times per week) and ribavirin (1 g daily) for 1 year in 17 Chinese patients who were negative for the human immunodeficiency virus. The HCV genotype consisted of a mixture of Western (genotypes 1, 2, and 3) and Chinese (genotypes 1 and 6) patterns. Quasi species were common (29%). Seven patients (41%) stopped treatment because of complications. Sustained HCV eradication was achieved until the end of treatment or for 24 months in 7 of 17 patients, respectively. A sustained response occurred in 50% of the patients completing treatment and occurred only in patients with genotypes 1, 3, and 6 but not with quasi species.
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Affiliation(s)
- Wing Y Au
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong.
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Abstract
Infection with hepatitis C virus (HCV) genotypes 1, 2, or 3 is widely distributed throughout the world and has been the focus of the majority of studies on the epidemiology and treatment of chronic hepatitis C. Infection with HCV genotypes 4 through 9 is prevalent in some geographic areas where the disease burden of chronic hepatitis C approaches endemic levels (eg, HCV genotype 4 in Egypt where there is an HCV infection prevalence of approximately 18%). This article reviews the existing literature, which suggests that chronic hepatitis C with genotypes 4 through 9 may exhibit epidemiologic, clinical, and treatment outcome differences from infection with genotypes 1, 2, or 3.
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Affiliation(s)
- Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Au WY, Liu CL, Lo CM, Fan ST, Lam CK. Living donor liver transplantation for hepatitis C related hepatocellular carcinoma in a haemophilia A patient. Haemophilia 2005; 11:405-7. [PMID: 16011595 DOI: 10.1111/j.1365-2516.2005.00945.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We report the first case of unrelated living liver transplantation for hepatitis C related hepatocellular carcinoma (HCC) in a Chinese patient with haemophilia A. The development of cirrhosis and HCC was insidious in this patient, who has previously failed interferon treatment despite low viral load and genotype 6a. With factor VIII and novoseven support, there were no operative complications and there was no need for blood transfusion. Postoperative pegulated interferon treatment resulted in viral clearance with no increased cellular rejection. The use of living donors represent a potential life saving therapeutic options for hepatitis C virus related complications in haemophiliac, especially in countries of organ shortage. Careful patient and donor choice, meticulous surgical expertise and proper counselling, however, are prudent requirements.
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Affiliation(s)
- W Y Au
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
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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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