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Usman A, Seerat I, Rizvi SB, Sheraz S, Yousaf HA. Outcome of Treatment in Children With Chronic Viral Hepatitis C: A Single Centre Study. Cureus 2022; 14:e21073. [PMID: 35155029 PMCID: PMC8825321 DOI: 10.7759/cureus.21073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2022] [Indexed: 11/05/2022] Open
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2
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Wan Z, Liu J, Hu F, Shui J, Li L, Wang H, Tang X, Hu C, Liang Y, Zhou Y, Cai W, Tang S. Evidence that the second human pegivirus (HPgV-2) is primarily a lymphotropic virus and can replicate independent of HCV replication. Emerg Microbes Infect 2020; 9:485-495. [PMID: 32100631 PMCID: PMC7054972 DOI: 10.1080/22221751.2020.1730247] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The second human pegivirus HPgV-2 is a novel blood-borne virus that is strongly associated with the hepatitis C virus (HCV) infection. However, the molecular evidence for their association as well as the natural history and tissue tropism of HPgV-2 remain to be elucidated. In this longitudinal study, a total of 753 patients including 512 HIV-1 and HCV co-infected patients were enrolled to characterize the natural history of HPgV-2 infection. Peripheral blood mononuclear cells (PBMCs) and liver biopsies were collected to determine the tissue tropism of HPgV-2 using immunohistochemical staining of the HPgV-2 antigen and in situ hybridization of HPgV-2 RNA. We documented both persistent HPgV-2 infection with the presence of HPgV-2 viral RNA and antibodies up to 4.6 years and resolved HPgV-2 infection, accompanied by a simultaneous decline of anti-HPgV-2 antibodies and clearance of HPgV-2 viremia. Furthermore, we observed the clearance of HCV, but not HPgV-2, by treatment with direct-acting antivirals (DAAs). Biochemical tests and pathological analyses did not reveal any indication of hepatic impairment caused by HPgV-2. HPgV-2 RNA and nonstructural antigen were detected in the lymphocytes, but not in the hepatocytes present in the liver biopsy samples. In addition, both positive- and negative-strand HPgV-2 RNAs were detected in PBMCs, especially in B cells. The present study is the first to provide evidence that HPgV-2 is a lymphotropic, but not a hepatotropic virus and that HPgV-2 replication is independent of HCV viremia. These new findings let us gain insights into the evolution and persistent infection of RNA viruses in humans.
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Affiliation(s)
- Zhengwei Wan
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Junwei Liu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Fengyu Hu
- Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jingwei Shui
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Linghua Li
- Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Haiying Wang
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiaoping Tang
- Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Chengguang Hu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuanhao Liang
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuanping Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Weiping Cai
- Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Shixing Tang
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China.,Dermatology Hospital, Southern Medical University, Guangzhou, People's Republic of China
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Luna JM, Saeed M, Rice CM. Taming a beast: lessons from the domestication of hepatitis C virus. Curr Opin Virol 2019; 35:27-34. [PMID: 30875640 PMCID: PMC6556422 DOI: 10.1016/j.coviro.2019.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/05/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Abstract
"What I cannot create, I do not understand." Richard Feynman may have championed reasoning from first principles in his famous blackboard missive, but he could just as well have been referring to the plight of a molecular virologist. What cannot be grown in a controlled laboratory setting, we cannot fully understand. The story of the laboratory domestication of hepatitis C virus (HCV) is now a classic example of virologists applying all manner of inventive skill to create cell-based models of infection in order to clarify prospective drug targets. In this review, we highlight key successes and failures that were instructive in achieving cell-based models for HCV studies and drug development. We also emphasize the lessons learned from the ∼40 year saga that may be applicable to viruses yet unknown and uncultured.
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Affiliation(s)
- Joseph M Luna
- The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States
| | - Mohsan Saeed
- The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States
| | - Charles M Rice
- The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States.
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Iwona BO, Karol P, Kamila CC, Pollak A, Hanna B, Agnieszka P, Andrzej H, Kosińska J, Płoski R, Tomasz L, Marek R. Next-generation sequencing analysis of new genotypes appearing during antiviral treatment of chronic hepatitis C reveals that these are selected from pre-existing minor strains. J Gen Virol 2018; 99:1633-1642. [PMID: 30394872 DOI: 10.1099/jgv.0.001160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Coinfection with more than one hepatitis C virus (HCV) genotype is common, but its dynamics, particularly during antiviral treatment, remain largely unknown. We employed next-generation sequencing (NGS) to analyse sequential serum and peripheral blood mononuclear cell (PBMC) samples in seven patients with transient presence or permanent genotype change during antiviral treatment with interferon and ribavirin. Specimens were collected right before the therapy initiation and at 2, 4, 6, 8, 12, 20, 24, 36, 44 and 48 weeks during treatment and 6 months after treatment ceased. A mixture of two different genotypes was detected in the pretreatment samples from five patients and the minor genotype constituted 0.02 to 38 %. A transient or permanent change of the predominant genotype was observed in six patients. In three cases genotype 3 was replaced as the predominant genotype by genotype 4, in two cases genotype 3 was replaced by genotype 1, and in one subject genotype 1 was replaced by genotype 4. The PBMC- and serum-derived sequences were frequently discordant with respect to genotype and/or genotype proportions. In conclusion, pre-existing minor HCV genotypes can be selected rapidly during antiviral treatment and become transiently or permanently predominant. In coinfections involving genotype 3, genotype 3 was eliminated first from both the serum and PBMC compartments. The PBMC- and serum-derived HCV sequences were frequently discordant with respect to genotype and/or genotype proportions, suggesting that they constitute separate compartments with their own dynamics.
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Affiliation(s)
- Bukowska-Ośko Iwona
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Perlejewski Karol
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Caraballo Cortés Kamila
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Agnieszka Pollak
- 2Institute of Physiology and Pathology of Hearing, 17 Mokra Street, Kajetany 05-830 Nadarzyn, Poland
| | - Berak Hanna
- 3Hospital for Infectious Diseases, 37 Wolska Street, 01-201 Warsaw, Poland
| | - Pawełczyk Agnieszka
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Horban Andrzej
- 3Hospital for Infectious Diseases, 37 Wolska Street, 01-201 Warsaw, Poland
- 4Department of Infectious Diseases, Warsaw Medical University, Warsaw, Poland
| | - Joanna Kosińska
- 5Department of Medical Genetics, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Rafał Płoski
- 5Department of Medical Genetics, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Laskus Tomasz
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Radkowski Marek
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
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Fabrizi F, Martin P, Lunghi G, Ponticelli C. Nosocomial Transmission of Hepatitis C virus Infection in Hemodialysis Patients: Clinical Perspectives. Int J Artif Organs 2018. [DOI: 10.1177/039139880002301205] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- F. Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital IRCCS, Milano - Italy
| | - P. Martin
- Division of Digestive Diseases and Dumont-UCLA Transplant Center, UCLA School of Medicine, Los Angeles, California - USA
| | - G. Lunghi
- Institute of Hygiene and Preventive Medicine, Maggiore Hospital IRCCS, Milano - Italy
| | - C. Ponticelli
- Division of Nephrology and Dialysis, Maggiore Hospital IRCCS, Milano - Italy
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Affiliation(s)
| | - S. Saab
- Department of Medicine and
- Dumont-UCLA Liver Transplant Program, Department of Surgery, University of California, Los Angeles Medical Center, Los Angeles, CA, USA
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Rodriguez C, Soulier A, Demontant V, Poiteau L, Mercier-Darty M, Bouvier-Alias M, Pawlotsky JM, Chevaliez S. A novel standardized deep sequencing-based assay for hepatitis C virus genotype determination. Sci Rep 2018; 8:4180. [PMID: 29520035 PMCID: PMC5843601 DOI: 10.1038/s41598-018-22614-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 02/26/2018] [Indexed: 01/06/2023] Open
Abstract
Hepatitis C virus (HCV) genotype and subtype (1a/1b) identification is needed to tailor anti-HCV therapy. Currently available methods accurately identify the genotype and differentiate subtypes 1a from 1b. However, these assays have not been designed to identify other HCV subtypes, nor to recognize mixed genotype/subtype infections, emphasizing the need for a high-resolution system based on phylogenetic analysis of reads obtained by deep sequencing of a relevant genome region. The aim of this study was to evaluate the performance of the Sentosa SQ HCV Genotyping Assay, a novel deep sequencing-based assay targeting the HCV nonstructural 5B (NS5B) region, in clinical samples from patients with an indication for anti-HCV therapy. A high concordance rate with Sanger sequencing of the NS5B region, the reference method, was found for genotype 1 to 6 determination, 1a/1b subtype identification, and genotype 4, 5 and 6 subtyping. Discrepancies were seen essentially for HCV genotype 2 subtyping. Overall, the performance of the deep sequencing-based assay in generating the genotypes/subtype information needed to tailor anti-HCV treatment was adequate in this study. Further improvements, such as a longer NS5B fragment analyzed and enriching the database of reference prototype strains used for subtype assignment would make it a method of choice for HCV genotyping and subtyping for future clinical practice and research.
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Affiliation(s)
- Christophe Rodriguez
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Alexandre Soulier
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Vanessa Demontant
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Lila Poiteau
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Mélanie Mercier-Darty
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Magali Bouvier-Alias
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM, U955, Créteil, France
| | - Stéphane Chevaliez
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
- INSERM, U955, Créteil, France.
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Distribution of HCV Genotypes and RNA Viral Load Along with Hemato-Biochemical Analysis of HCV Patients in Rahim Yar Khan, Okara and Toba Tek Singh Districts of Punjab, Pakistan. HEPATITIS MONTHLY 2017. [DOI: 10.5812/hepatmon.58442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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10
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Perumpail RB, Hahambis TA, Aggarwal A, Younossi ZM, Ahmed A. Treatment strategies for chronic hepatitis C prior to and following liver transplantation. World J Hepatol 2016; 8:69-73. [PMID: 26783422 PMCID: PMC4705454 DOI: 10.4254/wjh.v8.i1.69] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/30/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related liver disease is the leading indication for liver transplantation (LT) worldwide. However, HCV is an independent predictor of lower survival following LT, and recurrence of HCV post-LT is virtually universal. The historic standard of care during the interferon era of HCV therapy was expectant management-initiation of antiviral therapy in the setting of documented disease progression following LT. With the advent of new direct acting antiviral (DAA) therapies for HCV, the paradigm of expectant treatment for recurrent HCV infection post-LT is shifting. The safety, tolerability, and efficacy of DAAs, even among the sickest patients with advanced liver disease, enables treatment of HCV in the pre-transplant setting among LT waitlist registrants. Finally, emerging data are supportive of preemptive therapy with DAAs in liver transplant recipients as the preferred approach. Expectant management of HCV following LT can rarely be justified in the modern era of HCV therapy.
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Üçbilek E, Abayli B, Koyuncu MB, Midikli D, Gözüküçük S, Akdağ A, Özdoğan O, Altintaş E, Sezgin O. Distribution of hepatitis C virus genotypes among intravenous drug users in the Çukurova region of Turkey. Turk J Med Sci 2016; 46:66-71. [PMID: 27511336 DOI: 10.3906/sag-1411-169] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/07/2015] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND/AIM The most common hepatitis C virus (HCV) genotype in Turkey is genotype 1. However, there has not been a study about the distribution of HCV genotypes among intravenous drug users (IVDUs) in the Çukurova region of Turkey. This study was planned to understand if there is a difference between IVDUs and the normal population. MATERIALS AND METHODS Between May 2010 and May 2014, anti-HCV positive IVDUs who applied to the 6 hospitals in the Çukurova region of Turkey were included in this study. Their HCV genotypes were studied. RESULTS Ninety-seven anti-HCV positive IVDUs were screened in terms of HCV RNA and genotype. Ten were excluded from the study because their HCV RNA results were negative. Fifty-one of the 87 patients (58.6%) had genotype 3. Genotype 2 was detected in 26 (29.9%) and genotype 1 was detected in 10 (11.5%) patients. CONCLUSION HCV genotypes seem to be different between the normal population and IVDUs according to studies worldwide. Among IVDUs, we detected a dominance of genotype 3 and genotype 2, which is apparently different from the normal population. The reason for this difference can be simply explained by infection through shared needles. However, there may still be a different immunological response in IVDUs, the investigation of which may lead to further studies.
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Affiliation(s)
- Enver Üçbilek
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Bahri Abayli
- Department of Gastroenterology, Çukurova Dr. Aşkım Tüfekçi State Hospital, Adana, Turkey
| | - Mahmut Bakır Koyuncu
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Durdane Midikli
- Department of Infectious Diseases, Adana State Hospital, Adana, Turkey
| | - Süveyda Gözüküçük
- Department of Infectious Diseases, Dr. Ekrem Tok Psychiatry Hospital, Adana, Turkey
| | - Alper Akdağ
- Department of Infectious Diseases, Ceyhan State Hospital, Adana, Turkey
| | - Osman Özdoğan
- Department of Gastroenterology, Tarsus State Hospital, Mersin, Turkey
| | - Engin Altintaş
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
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Analysis of Hepatitis C Virus Genotype 1b Resistance Variants in Japanese Patients Treated with Paritaprevir-Ritonavir and Ombitasvir. Antimicrob Agents Chemother 2015; 60:1106-13. [PMID: 26643326 PMCID: PMC4750684 DOI: 10.1128/aac.02606-15] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023] Open
Abstract
Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance-conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR24) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients.
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Janahi EM, Al-Mannai M, Singh H, Jahromi MM. Distribution of Hepatitis C Virus Genotypes in Bahrain. HEPATITIS MONTHLY 2015; 15:e30300. [PMID: 26977163 PMCID: PMC4774338 DOI: 10.5812/hepatmon.30300] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/12/2015] [Accepted: 08/04/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Approximately 170 million people are infected with Hepatitis C virus (HCV) worldwide, making it one of the world's major infectious diseases. There are no published population based studies about the prevalence of HCV genotypes in Bahrain. OBJECTIVES Therefore, the aim of the present study was to investigate the prevalence and distribution of HCV genotypes and subtypes among a large sample of patients with chronic HCV infection in Bahrain. PATIENTS AND METHODS Serum samples were collected from 202 HCV positive patients; of them 128 had a viral load (> 500 IU/mL) suitable for the type-specific genotyping assay. Gender-wise and age-wise differences in the distribution of HCV genotypes were determined by Chi Square and Fisher's Exact tests. RESULTS The predominant genotype among Bahraini patients was type 1 (36.71%), followed by genotypes 3 and 4 (15.6% each) and the lowest frequency was found for genotype 2 (3.9%). Among genotype 1, subtype 1b had the highest frequency (21.09%), followed by subtype 1a (14.06%). Among genotype 3, subtype 3a had the highest frequency (11.72%), while among genotype 4, most of subtypes were undetermined. The frequency of all different HCV genotypes was higher in male patients compared to female patients. Genotype 1 was most common in the age group of 51 - 60 years (38.3%), genotype 2 in 21 - 30 years (60%) and genotype 3 in 51 - 60 years (30%), while genotype 4 was most frequent among the age group > 61 (40%). CONCLUSIONS The most common HCV genotype in Bahrain was subtype 1b followed by 1a and 3a. Further studies involving sources of transmission in Bahrain are required to enhance control measures for HCV infection.
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Affiliation(s)
- Essam M. Janahi
- Department of Biology, College of Science, University of Bahrain, Sakhir, Bahrain
- Corresponding Author: Essam M. Janahi, Department of Biology, College of Science, University of Bahrain, Zallaq, Bahrain. Tel: +973-1743742511, Fax: +973-17449662, E-mail:
| | - Mariam Al-Mannai
- Department of Mathematics, College of Science, University of Bahrain, Sakhir, Bahrain
| | - Hemlata Singh
- Department of Biology, College of Science, University of Bahrain, Sakhir, Bahrain
| | - Mohamed M. Jahromi
- Salmaniya Medical Complex, Ministry of Health, Manama, Bahrain and Dasman Diabetes Institute, Kuwait City, Kuwait
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Farag MMS, Sofy AR, Mousa AA, Ahmed MA, Alganzory MR. Molecular Assay and Genotyping of Hepatitis C Virus among Infected Egyptian and Saudi Arabian Patients. Virology (Auckl) 2015; 6:1-10. [PMID: 26512201 PMCID: PMC4603572 DOI: 10.4137/vrt.s32016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/03/2015] [Accepted: 09/10/2015] [Indexed: 01/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a major health problem recognized globally. HCV is a common cause of liver fibrosis that may lead to liver cirrhosis or hepatocellular carcinoma. The aim of this study was to estimate the prevalence of HCV infection and genotyping among Egyptian and Saudi Arabian chronic patients using different molecular techniques. HCV RNA viral load was assessed by real-time polymerase chain reaction (RT-PCR) technology. For HCV genotyping, RT-PCR hybridization fluorescence-based method and reverse hybridization line probe assay (INNO-LiPA) were used. A total of 40 anti-HCV-positive patients with chronic hepatitis C were examined for HCV RNA, genotyping, and different laboratory investigations. In the present study, HCV genotypes 4, mixed 4.1b, and 1 were detected in patients of both countries, while genotype 2 was only detected in Saudi Arabian patients. Genotyping methods for HCV showed no difference in the classification at the genotype level. With regard to HCV subtypes, INNO-LiPA assay was a reliable test in HCV genotyping for the detection of major genotypes and subtypes, while RT-PCR-based assay was a good test at the genotype level only. HCV genotype 4 was found to be the predominant genotype among Egyptian and Saudi Arabian chronic patients. In conclusion, data analysis for detecting and genotyping HCV was an important factor for understanding the epidemiology and treatment strategies of HCV among Egyptian and Saudi Arabian chronic patients.
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Affiliation(s)
- Mohamed MS Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed R Sofy
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Adel A Mousa
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Mohamed A Ahmed
- Clinical Pathology Department, Military Medical Academy, Cairo, Egypt
| | - Mohamed R Alganzory
- Basic Science Department, College of Dentistry, Majma’ah University, Al Majma’ah, Kingdom of Saudi Arabia
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16
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Cuypers L, Li G, Libin P, Piampongsant S, Vandamme AM, Theys K. Genetic Diversity and Selective Pressure in Hepatitis C Virus Genotypes 1-6: Significance for Direct-Acting Antiviral Treatment and Drug Resistance. Viruses 2015; 7:5018-39. [PMID: 26389941 PMCID: PMC4584301 DOI: 10.3390/v7092857] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/22/2015] [Accepted: 09/01/2015] [Indexed: 12/20/2022] Open
Abstract
Treatment with pan-genotypic direct-acting antivirals, targeting different viral proteins, is the best option for clearing hepatitis C virus (HCV) infection in chronically infected patients. However, the diversity of the HCV genome is a major obstacle for the development of antiviral drugs, vaccines, and genotyping assays. In this large-scale analysis, genome-wide diversity and selective pressure was mapped, focusing on positions important for treatment, drug resistance, and resistance testing. A dataset of 1415 full-genome sequences, including genotypes 1-6 from the Los Alamos database, was analyzed. In 44% of all full-genome positions, the consensus amino acid was different for at least one genotype. Focusing on positions sharing the same consensus amino acid in all genotypes revealed that only 15% was defined as pan-genotypic highly conserved (≥99% amino acid identity) and an additional 24% as pan-genotypic conserved (≥95%). Despite its large genetic diversity, across all genotypes, codon positions were rarely identified to be positively selected (0.23%-0.46%) and predominantly found to be under negative selective pressure, suggesting mainly neutral evolution. For NS3, NS5A, and NS5B, respectively, 40% (6/15), 33% (3/9), and 14% (2/14) of the resistance-related positions harbored as consensus the amino acid variant related to resistance, potentially impeding treatment. For example, the NS3 variant 80K, conferring resistance to simeprevir used for treatment of HCV1 infected patients, was present in 39.3% of the HCV1a strains and 0.25% of HCV1b strains. Both NS5A variants 28M and 30S, known to be associated with resistance to the pan-genotypic drug daclatasvir, were found in a significant proportion of HCV4 strains (10.7%). NS5B variant 556G, known to confer resistance to non-nucleoside inhibitor dasabuvir, was observed in 8.4% of the HCV1b strains. Given the large HCV genetic diversity, sequencing efforts for resistance testing purposes may need to be genotype-specific or geographically tailored.
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Affiliation(s)
- Lize Cuypers
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, Leuven 3000, Belgium.
| | - Guangdi Li
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, Leuven 3000, Belgium.
- Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Changsha 410011, China.
| | - Pieter Libin
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, Leuven 3000, Belgium.
- Artificial Intelligence Lab, Vrije Universiteit Brussel, Pleinlaan 2, Brussels 1050, Belgium.
| | - Supinya Piampongsant
- Department of Electrical Engineering ESAT, STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, University of Leuven, Kasteelpark Arenberg 10, Heverlee 3001, Belgium.
| | - Anne-Mieke Vandamme
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, Leuven 3000, Belgium.
- Center for Global Health and Tropical Medicine, Microbiology Unit, Institute for Hygiene and Tropical Medicine, University Nova of Lisboa, Rua da Junqueira 100, Lisbon 1349-008, Portugal.
| | - Kristof Theys
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, Leuven 3000, Belgium.
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Aziz H, Raza A, Irfan J. Optimum predictors of therapeutic outcome in HCV patients in Pakistan. J Med Virol 2015; 88:100-8. [PMID: 26103918 DOI: 10.1002/jmv.24305] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2015] [Indexed: 12/30/2022]
Abstract
Hepatitis C virus (HCV) constitutes a major public health issue in Pakistan. Interferon α and ribavirin is used widely in routine practice in HCV infected patients in Pakistan.Treatment prediction is an important tool in therapy management. The present study aims to evaluate trends of predictive variables of treatment outcome in patients with different genotypes. The analysis comprised of 921 patients infected with different HCV genotypes. All the patients received IFN α-2b combined with ribavirin for 24 weeks. Overall, 60.2% patients achieved Sustained virologic response (SVR). In females sustained virologic response (SVR) was higher in age group <40 years (77.2%) than ≥40-50 years (60%) but in male SVR was almost equal in both age groups. We also found higher SVR with low pretreatment viral load (72.4%, P < 0.0001). Sustained Virologic Response in genotype 3a was 63.1%, 3b was 55%, 1a was 36.3% and 1b was 35% 3a +3b was 55.0% and 1a+3a was 42.9%. According to multivariable logistic regression analysis age < 40 years (2.0; 95%CI, 1.49-2.84; P = 0.0001), low pretreatment RNA level<800,000 IU/ml (4.0; 95%CI, 2.64-6.17; P = 0.0001), early virologic response at week 12 (12.3; 95%CI, 8.18-18.58; P < 0.0001) and non-fatty liver (2.5; 95%CI, 3.6-6.2; P = 0.005) showed significance for SVR. Nucleotide substitution in 5'UTR before treatment failed to show any characteristic pattern that has correlation with sustained response. Subtype 3a showed 95% presence among patients with age <40 years while older patients showed 79.9%.
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Affiliation(s)
- Hafsa Aziz
- Nuclear Medicine Oncology and Radiotherapy Institute, Islamabad, Pakistan
| | - Abida Raza
- Nuclear Medicine Oncology and Radiotherapy Institute, Islamabad, Pakistan
| | - Javaid Irfan
- Nuclear Medicine Oncology and Radiotherapy Institute, Islamabad, Pakistan
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Rossi LMG, Escobar-Gutierrez A, Rahal P. Advanced molecular surveillance of hepatitis C virus. Viruses 2015; 7:1153-88. [PMID: 25781918 PMCID: PMC4379565 DOI: 10.3390/v7031153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/05/2015] [Accepted: 02/20/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is an important public health problem worldwide. HCV exploits complex molecular mechanisms, which result in a high degree of intrahost genetic heterogeneity. This high degree of variability represents a challenge for the accurate establishment of genetic relatedness between cases and complicates the identification of sources of infection. Tracking HCV infections is crucial for the elucidation of routes of transmission in a variety of settings. Therefore, implementation of HCV advanced molecular surveillance (AMS) is essential for disease control. Accounting for virulence is also important for HCV AMS and both viral and host factors contribute to the disease outcome. Therefore, HCV AMS requires the incorporation of host factors as an integral component of the algorithms used to monitor disease occurrence. Importantly, implementation of comprehensive global databases and data mining are also needed for the proper study of the mechanisms responsible for HCV transmission. Here, we review molecular aspects associated with HCV transmission, as well as the most recent technological advances used for virus and host characterization. Additionally, the cornerstone discoveries that have defined the pathway for viral characterization are presented and the importance of implementing advanced HCV molecular surveillance is highlighted.
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Affiliation(s)
- Livia Maria Gonçalves Rossi
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
| | | | - Paula Rahal
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
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Maksyutov RA, Gavrilova EV, Maksyutov AZ, Kanev AN. Genotyping of hepatitis B and C virus Russian isolates for reference serum panel construction. J Med Virol 2015; 87:1192-8. [PMID: 25758235 DOI: 10.1002/jmv.24170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2015] [Indexed: 12/18/2022]
Abstract
Approximately 2% and 5% of the world human population is estimated to be infected with HCV and HBV, respectively. Reference panels of HCV and HBV serum samples with defined genotypes and serotypes is necessary for monitoring of the specificity and sensitivity of diagnostic test kits. The aim of this study was to determine genotypes/serotypes of HBV and HCV circulating in Russia in order to construct a panel of reference sera containing these HCV genotypes and HBV serotypes. A total of 343 HBsAg-positive and 207 anti-HCV positive serum samples were collected from patients with HBV and HCV infection from different cities between years 2002 and 2010 in St. Petersburg, Krasnodar, Nizhny Novgorod, Novosibirsk, Barnaul, Gorno-Altaisk, and Khabarovsk. HBV DNA was found in 76.4% of HBsAg positive samples by PCR for the S gene and HCV RNA was found in 71.5, 70.0, and 64.7% of anti-HCV positive samples in the 5'UTR, Core, and NS5B regions, respectively. The prevalence and proportion of HBV genotype/serotype associations were as follows: A/adw2, 2.1%; D/ayw2, 54.0%; D/ayw3, 43.1%; D/adw2, 0.7%. A new combination of genotype D and adw2 serotype was discovered. The distribution of HCV genotypes was the following: 43.6%, b; 3.8%, 2a; and 52.6%, 3a. Russian National reference panels of HBV and HCV lyophilized sera were developed to monitor specificity and sensitivity of approved kits and for the certification of newly developed assays.
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Affiliation(s)
- Rinat A Maksyutov
- State Research Center of Virology and Biotechnology "Vector", Koltsovo, Novosibirsk Region, Russia
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Dong Y, Qiu C, Xia X, Wang J, Zhang H, Zhang X, Xu J. Hepatitis B virus and hepatitis C virus infection among HIV-1-infected injection drug users in Dali, China: prevalence and infection status in a cross-sectional study. Arch Virol 2015; 160:929-36. [PMID: 25616842 DOI: 10.1007/s00705-014-2311-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 12/10/2014] [Indexed: 01/21/2023]
Abstract
To assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and to investigate their mutual influences on infection status among human immunodeficiency virus type 1 (HIV-1)-seropositive injection drug users (IDUs). A cross-sectional study was conducted among HIV infected IDUs in Dali, China. The participants were tested for serological markers of HBV and HCV infection, alanine transaminase (ALT) activity and CD4(+) T cell count. HCV genotype was determined by sequencing. Of 529 patients, 498 (94.1 %) HIV infected IDUs agreed to participate. The overall prevalence of HCV infection (anti-HCV antibody positive) and spontaneous HCV clearance were 90.8 % (452/498) and 21.5 % (97/452), respectively. Of 411 subjects who had not received HBV vaccine, 296 (72.0 %) were positive for antibody against HBV core antigen (HBcAb), while 274 (66.7 %) were positive for both HCV antibody and HBcAb. HBV antigens were detected in 52 of the HBV-infected subjects (17.6 %). HCV clearance was associated with HBV antigenemia (p = 0.0002) and higher CD4(+) T cell count (p = 0.0294). Resolved HBV infection was associated with HCV genotype 3 (p = 0.0365). HBV and HCV infection are highly prevalent and mutually influence infection status in HIV-1 infected IDUs in Dali, China.
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Affiliation(s)
- Yuan Dong
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Research Bldg, Rm 308, 2901 Caolang Road, Jinshan District, Shanghai, 201508, China
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Morel V, Duverlie G, Brochot E. Patients eligible for treatment with simeprevir in a French center. J Clin Virol 2014; 61:149-51. [PMID: 25027573 DOI: 10.1016/j.jcv.2014.06.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/24/2014] [Accepted: 06/24/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Simeprevir (Olysio(®)), a second-wave protease inhibitor recently approved for the treatment of chronic hepatitis C, is not indicated in patients with genotype 1a strain harboring the Q80K protease mutation. Phase 2 and 3 studies on this molecule mainly focused on North American patients and the prevalence of Q80K is particularly high in the USA (around 50%). The prevalence of this mutation in other parts of the world is currently unknown. OBJECTIVES The purpose of our study was to perform a detection of this mutation in a single PCR technique and to study the prevalence of this Q80K mutation in a non U.S. population. We can thus estimate the proportion of HCV positive patients who can be treated with simeprevir. STUDY DESIGN We conducted a meta-analysis of response rates in the presence or absence of this mutation in randomized trials and then describe a simple and reliable method to detect this mutation. We also examined bilirubin levels in our cohort of 95 HCV genotype 1a patients. RESULTS Ten patients (10.5%) had a Q80K mutation and 12 patients exhibited bilirubin levels above the upper limit of normal at baseline. In our cohort, 21 patients (22%) were therefore ineligible for treatment with simeprevir. The prevalence of this mutation seems to be much lower in European patients. CONCLUSION In conclusion, before considering treatment with simeprevir, physicians must be able to screen for the Q80K mutation.
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Affiliation(s)
- Virginie Morel
- Department of Virology, Amiens University Medical Center, Amiens, France; Virology Research Unit, EA 4294, Jules Verne University of Picardie, Amiens, France
| | - Gilles Duverlie
- Department of Virology, Amiens University Medical Center, Amiens, France; Virology Research Unit, EA 4294, Jules Verne University of Picardie, Amiens, France
| | - Etienne Brochot
- Department of Virology, Amiens University Medical Center, Amiens, France; Virology Research Unit, EA 4294, Jules Verne University of Picardie, Amiens, France.
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Afridi SQ, Ali MM, Awan F, Zahid MN, Afridi IQ, Afridi SQ, Yaqub T. Molecular epidemiology and viral load of HCV in different regions of Punjab, Pakistan. Virol J 2014; 11:24. [PMID: 24512668 PMCID: PMC3925129 DOI: 10.1186/1743-422x-11-24] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 02/07/2014] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) is highly infectious pathogen which is responsible for causing Hepatitis around 200 million individuals worldwide. In Pakistan, 4.7% of HCV prevalence has been reported and HCV genotype 3a has been found to be the major source of infection in Pakistan but still there is lack of information on distribution of HCV genotypes and viral load in various geographical regions of Pakistan. Therefore, current study was designed to determine distribution of HCV genotypes as well viral load in different areas of Punjab province of Pakistan. FINDINGS A total of 995 serum samples were taken from those individuals in which antibodies against HCV were detected through ELISA, from different regions of Punjab i.e. Lahore 317(31.85%), Faisalabad 70(7.03%), Gujranwala 129(12.96%), Gujrat 106(10.65%), Sialkot 94(9.44%), Sargodha 60(6.03%), Mandibaha-ud-din 135(13.56%), Jhang 86(8.64%). Qualitative PCR was performed to determine viral load and genotyping was performed using Nested PCR. Chi-square test was used to determine the age and sex-wise prevalence of HCV. Out of 995 samples, 888 samples were found positive for HCV RNA. In all regions, genotype 3a showed highest prevalence (82.81%) followed by genotype 1 (3.41%), mixed genotypes (2.41%), genotype 2 (0.50%), genotype 5 (0.1%) and unclassified genotypes (10.75%). Viral load in 29.5% patients infected with genotype 3a was less than 600,000 IU/mL, while it was between 600,000-800,000 IU/mL in 27.9% patients and 25.22% patients had more than 800,000 IU/mL viral load. CONCLUSION HCV genotype 3a is the most prevalent genotype in various regions of Punjab. Viral load of HCV patients in these different regions of Punjab are reported for the first time. Moreover, based upon these results the Patients having viral load below 800,000 IU/mL would be expected to show better response of anti-HCV therapy.
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Aljumah AA, Murad MH. Pegylated versus standard interferon plus ribavirin in chronic hepatitis C genotype 4: A systematic review and meta-analysis. Hepatol Res 2013; 43:1255-63. [PMID: 23458104 DOI: 10.1111/hepr.12084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 01/23/2013] [Accepted: 01/29/2013] [Indexed: 02/08/2023]
Abstract
AIM Treatment of hepatitis C genotype 4 (HCV-G4) with pegylated interferon (PEG IFN) has not been adequately studied and is considered to be challenging. The aim of this meta-analysis is to systematically review and evaluate the effectiveness of 48 weeks of combined PEG IFN plus ribavirin (RBV) compared to standard interferon (IFN) plus RBV. The outcome of interest is sustained virological response (SVR). METHODS We searched for eligible randomized controlled trials (RCT) through May 2012. Random effects meta-analysis was used to pool the risk ratio (RR) of achieving SVR across trials. RESULTS Five RCT enrolling 386 patients were included. The PEG IFN/RBV group had increased likelihood of achieving SVR (RR = 1.51, 95% confidence interval [CI] = 1.08-2.10). SVR was significantly higher in PEG IFN-α-2a compared to the -α-2b group (P = 0.02). There was no statistically significant effect of ribavirin dosage on SVR (P = 0.55). The quality of evidence was moderate overall and limited by heterogeneity. CONCLUSION In treatment-naive patients with HCV-G4, treatment with PEG IFN plus RBV achieves higher SVR rate than treatment with IFN plus RBV.
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Affiliation(s)
- Abdulrahman A Aljumah
- Hepatology Division, Department of Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City and King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
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Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 2013; 19:7896-7909. [PMID: 24307784 PMCID: PMC3848138 DOI: 10.3748/wjg.v19.i44.7896] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/11/2013] [Accepted: 10/13/2013] [Indexed: 02/06/2023] Open
Abstract
This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus (HCV) infection over the last few decades. The information based on published literature provides an update on these two aspects of HCV. HCV infection, previously called blood transmitted non-A, non-B infection, is prevalent globally and poses a serious public health problem worldwide. The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction (PCR) technique. Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles. Moreover, multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes. In contrast to previous methods, the newly developed assays are not only fast and economic, but also resolve the problem of the window period as well as differentiate present from past infection. HCV is a non-cytopathic virus, thus, its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress, insulin resistance and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV-quasispecies and several metabolic factors regulating liver metabolism. HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.
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Bokharaei-Salim F, Keyvani H, Monavari SH, Alavian SM, Fakhim S, Nasseri S. Distribution of hepatitis C virus genotypes among azerbaijani patients in capital city of iran-tehran. HEPATITIS MONTHLY 2013; 13:e13699. [PMID: 24282427 PMCID: PMC3830518 DOI: 10.5812/hepatmon.13699] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Revised: 07/23/2013] [Accepted: 08/07/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Determination of the Hepatitis C virus (HCV) genotype distributed in a particular area has an important role on public health throughout the world. OBJECTIVES The aim of this study was to determine the frequency of HCV genotypes in Azerbaijani patients. PATIENTS AND METHODS From March 2010 until March 2012, 235 Azerbaijani patients with established chronic hepatitis C, referred to Hospitals related to Iran University of Medical Sciences and Tehran Hepatitis Center, Clinical department of Baqiyatallah Research Center for Gastroeneterology and Liver Disease, were enrolled in this cross sectional study. About 5 mL of peripheral blood was collected from patients and after separation of plasma, viral RNA extracted. HCV-RNA were amplified by RT-nested PCR using primers from the 5´-UTR and genotyped by RFLP assay, and then HCV genotypes were confirmed using sequencing of cloned PCR products into pJET1.2/blunt cloning vector. RESULTS HCV genotyping of positive plasma samples demonstrated that predominant HCV subtype was noted for 1b (71.1%) followed by subtype 3a (17.0%), genotype 2 (6.8%), 1a (1.7%), and mixed infection (3.4%). The mean ± SD age of patients was 37.3 ± 11.8 (range: 2-63) years. Out of 235 patients, 139 (59.1%) were male. The frequency of HCV subtype 3a was higher in patients under 40 years old (3a: 18.1% vs. 15.0%), and subtype 3a was higher in male patients (3a: 18.7% vs. 14.6%). CONCLUSIONS The current study shows that the predominant HCV genotype among Azerbaijani patients with established chronic hepatitis C is subtype 1b (71.1%) followed by subtype 3a (17.0%).
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Zhou JH, Su JH, Chen HT, Zhang J, Ma LN, Ding YZ, Stipkovits L, Szathmary S, Pejsak Z, Liu YS. Clustering of low usage codons in the translation initiation region of hepatitis C virus. INFECTION GENETICS AND EVOLUTION 2013; 18:8-12. [DOI: 10.1016/j.meegid.2013.03.043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Revised: 02/26/2013] [Accepted: 03/24/2013] [Indexed: 01/02/2023]
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Koutsoudakis G, Pérez-del-Pulgar S, González P, Crespo G, Navasa M, Forns X. A Gaussia luciferase cell-based system to assess the infection of cell culture- and serum-derived hepatitis C virus. PLoS One 2012; 7:e53254. [PMID: 23300900 PMCID: PMC3534054 DOI: 10.1371/journal.pone.0053254] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Accepted: 11/27/2012] [Indexed: 02/05/2023] Open
Abstract
Robust replication of hepatitis C virus (HCV) in cell culture occurs only with the JFH-1 (genotype 2a) recombinant genome. The aim of this study was to develop a system for HCV infection quantification analysis and apply it for the selection of patient sera that may contain cell culture infectious viruses, particularly of the most clinically important genotype 1. Initially, a hepatoma cell line (designated Huh-7.5/EG(4A/4B)GLuc) was generated that stably expressed the enhanced green fluorescent protein (EGFP) fused in-frame to the secreted Gaussia luciferase via a recognition sequence of the viral NS3/4A protease. Upon HCV infection, NS3/4A cleaved at its signal and the Gaussia was secreted to the culture medium, thus facilitating the infection quantification. The Huh-7.5/EG(4A/4B)GLuc cell line provided a rapid and highly sensitive quantification of HCV infection in cell culture using JFH-1-derived viruses. Furthermore, the Huh-7.5/EG(4A/4B)GLuc cells were also shown to be a suitable host for the discovery of anti-HCV inhibitors by using known compounds that target distinct stages of the HCV life cycle; the Ź-factor of this assay ranged from 0.72 to 0.75. Additionally, eighty-six sera derived from HCV genotype 1b infected liver transplant recipients were screened for their in vitro infection and replication potential. Approximately 12% of the sera contained in vitro replication-competent viruses, as deduced by the Gaussia signal, real time quantitative PCR, immunofluorescence and capsid protein secretion. We conclude that the Huh-7.5/EG(4A/4B)GLuc cell line is an excellent system not only for the screening of in vitro replication-competent serum-derived viruses, but also for the subsequent cloning of recombinant isolates. Additionally, it can be utilized for high-throughput screening of antiviral compounds.
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Affiliation(s)
- George Koutsoudakis
- Liver Unit, Institut D'Investigacions Biomèdics August Pi i Sunyer, Centro de Investigación Biomédica en Red: Enfermedades Hepáticas y Digestivas, Hospital Clínic, Barcelona, Spain.
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González-Carmona MA, Quasdorff M, Vogt A, Tamke A, Yildiz Y, Hoffmann P, Lehmann T, Bartenschlager R, Engels JW, Kullak-Ublick GA, Sauerbruch T, Caselmann WH. Inhibition of hepatitis C virus RNA translation by antisense bile acid conjugated phosphorothioate modified oligodeoxynucleotides (ODN). Antiviral Res 2012; 97:49-59. [PMID: 23142319 DOI: 10.1016/j.antiviral.2012.10.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 10/26/2012] [Accepted: 10/28/2012] [Indexed: 01/22/2023]
Abstract
BACKGROUND The 5'-noncoding region (5'NCR) of the HCV-genome comprises an internal ribosome entry site essential for HCV-translation/replication. Phosphorothioate oligodeoxynucleotides (tS-ODN) complementary to this region can inhibit HCV-translation in vitro. In this study, bile acid conjugated tS-ODN were generated to increase cell-selective inhibition of 5'NCR-dependent HCV-translation. METHODS Different bile acid conjugated tS-ODN complementary to the HCV5'NCR were selected for their inhibitory potential in an in vitro transcription/translation assay. To analyze OATP (organic anion transporting polypeptides)-selective uptake of bile acid conjugated ODN, different hepatoma cells were stably transfected with the OATP1B1-transporter and primary human hepatocytes were used. An adenovirus encoding the HCV5'NCR fused to the luciferase gene (Ad-GFP-NCRluc) was generated to quantify 5'NCR-dependent HCV gene expression in OATP-overexpressing hepatoma cells and in vivo. RESULTS A 17mer phosphorothioate modified ODN (tS-ODN4_13) complementary to HCV5'NCR was able to inhibit 5'NCR-dependent HCV-translation in an in vitro transcription/translation test system by more than 90% and it was also effective in Huh7-cells containing the HCV subgenomic replicon. Conjugation to taurocholate (tS-ODN4_13T) significantly increased selective ODN uptake by primary human hepatocytes and by OATP1B1-expressing HepG2-cells compared to parental HepG2-cells. Correspondingly, tS-ODN4_13T significantly inhibited HCV gene expression in liver-derived OATP1B1-expressing HepG2- or CCL13-cells up to 70% compared to unconjugated tS-ODN and compared to mismatch taurocholate coupled tS-ODN. In vivo, tS-ODN4_13T showed also a trend to block 5'NCR-dependent HCV gene expression. CONCLUSIONS The tested taurocholate conjugated 17mer antisense ODN complementary to HCV5'NCV showed an increased and selective uptake by hepatocytes and liver-derived cells through OATP-mediated transport resulting in enhanced specific inhibition of HCV gene expression in vitro and in vivo. Thus, this novel approach may represent a promising strategy to improve antisense approaches with ODN in the control of hepatitis C infection.
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Differential reactivity to IMPDH2 by anti-rods/rings autoantibodies and unresponsiveness to pegylated interferon-alpha/ribavirin therapy in US and Italian HCV patients. J Clin Immunol 2012; 33:420-6. [PMID: 23100146 DOI: 10.1007/s10875-012-9827-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 10/17/2012] [Indexed: 02/06/2023]
Abstract
PURPOSE Autoantibodies to cytoplasmic structures called rods and rings (RR) are primarily specific to patients with hepatitis C virus (HCV) infection treated with pegylated interferon-alpha/ribavirin (IFN/R). Our aim is to examine anti-RR antibodies specificity and correlation with the response to IFN/R therapy in two independent cohorts (US and Italy) of HCV patients. METHODS Sera from the US cohort (n = 47) and the Italian cohort (n = 46) pre-selected for anti-RR antibodies were analyzed by immunofluorescence and radioimmunoprecipitation. The prevalence and titers of anti-RR were analyzed for correlation with the response to IFN/R therapy. RESULTS In the US cohort, anti-RR antibodies were more frequently non-responders to IFN/R (71 % vs 29 % responders). Titers in responder patients (n = 11) were ≤1:3200, whereas titers in non-responder patients (n = 27) reached 1:819,200 (p = 0.0016). In the Italian cohort, anti-RR titers ranged from 1:200 to >1:819,200 and only relapsers had the highest anti-RR titers. Radioimmunoprecipitation demonstrated that anti-RR autoantibodies were mainly anti-inosine monophosphate dehydrogenase 2 (IMPDH2) - 96 % in the Italian cohort vs. 53 % in the US cohort. CONCLUSIONS In the two cohorts analyzed, the anti-IMPDH2 response as a component of the anti-RR response is much more prominent in the Italian cohort. The reason for the difference between the US and Italian cohorts is unclear but it possibly illustrates the heterogeneity in response and the overall negative correlation between the production of these autoantibodies and response to IFN/R therapy. Patients with high titer anti-RR antibodies are either relapsers (Italian) or non-responders/relapsers (US).
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New insights into hepatitis C virus infection in the tribal-dominant part of Northeast India. Arch Virol 2012; 157:2083-93. [PMID: 22791109 DOI: 10.1007/s00705-012-1374-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Accepted: 05/06/2012] [Indexed: 01/22/2023]
Abstract
Northeast India is known for the demographic heterogeneity of its tribal population, but there is no information about hepatitis C virus infection and associated risk factors. Anti-HCV was measured, HCV-RNA was detected based on the 5' UTR-core region, and genotyping was done by direct sequencing of the NS5b region. Antibodies to HCV were found in 13.7 % of the samples tested (96 out of 700), while HCV-RNA was positive in 73 % of the samples (70 out of 96) and in 5 out of 385 cases of occult HCV infection. Genotypes 1 to 4 were found respectively in 14.6, 7.3, 20, 30.8 %, and genotype 6 in 13.6 %, of the 75 HCV isolates. In acute viral hepatitis (AVH), the most prevalent genotype was 2a (28.6 %), while it was 4a (28 %) in chronic hepatitis C (CHC) and 29.4 % in cirrhosis. Males were more prone than females to HCV infection, and the highest numbers of cases of HCV infection were recorded in the age group of 40-49 years. The major risk factors were intravenous drug abuse (IVDU) (34.6 %), multiple sexual partners (20 %) and contact with professional barbers (38.6 %). The seroprevalence of HCV in Northeast India is higher than in the rest of India. This study highlights the fact that geographical variations occur with respect to HCV genotypes, which could influence the course and progress of different type of liver diseases seen in India.
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Oh DJ, Park YM, Seo YI, Lee JS, Lee JY. Prevalence of hepatitis C virus infections and distribution of hepatitis C virus genotypes among Korean blood donors. Ann Lab Med 2012; 32:210-5. [PMID: 22563557 PMCID: PMC3339302 DOI: 10.3343/alm.2012.32.3.210] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Revised: 01/27/2012] [Accepted: 02/08/2012] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) remains a worldwide health-care burden. Prevalence rates vary and the distribution of genotypes depends on geographical location. Here, the recent prevalence of HCV infections and distribution of HCV genotypes among Korean blood donors were studied. METHODS Between February 2005 and December 2009, a total of 11,064,532 donors were screened for anti-HCV and 11,412,690 donors were screened for HCV RNA. HCV genotyping was conducted for 748 blood donors with HCV RNA by using the line probe assay (VERSANT HCV Genotype 2.0 Assay, Bayer Healthcare, USA) after amplification of the 5'-untranslated and core regions of the genome. RESULTS The anti-HCV prevalence was 0.16% (17,250/11,064,532). HCV RNA was detected in 959 out of the 11,412,690 donors (8.4/100,000). HCV RNA was more prevalent among women, donors who resided at harbor sites, and first-time donors. In addition, the prevalence of HCV RNA increased with age. The genotypes of 740 out of the 748 tested donors (98.9%) were identified. HCV genotype 1b (47.7%) and 2a/2c (35.0%) were dominant. Genotypes 2 (7.6%), 2b (2.3%), 3a (1.6%), 1a (1.3%), 1 (0.9%), 2v (0.5%), 1v (0.1%), and 3 (0.1%) were also identified. Genotype 4a/4c/4d (0.1%) was detected for the first time in one Korean blood donor. CONCLUSIONS The distribution of HCV genotypes in Korea has not changed remarkably, with the exception of genotype 4a/4c/4d. A periodic study to monitor the prevalence of HCV infections and the distribution of HCV genotypes is required to identify emerging genotypes in Korea.
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Affiliation(s)
- Deok Ja Oh
- Central Blood Laboratory Center, Korean Red Cross, Seoul, Korea.
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Ullah S, Shah MAA, Riaz N. Recent Advances in Development of DNA Vaccines Against Hepatitis C virus. INDIAN JOURNAL OF VIROLOGY : AN OFFICIAL ORGAN OF INDIAN VIROLOGICAL SOCIETY 2012; 23:253-60. [PMID: 24293811 DOI: 10.1007/s13337-012-0058-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Accepted: 02/03/2012] [Indexed: 01/28/2023]
Abstract
Hepatitis C is one of the foremost challenging diseases all over the world. No vaccine has been developed, yet against Hepatitis C virus (HCV). This is partly due to the high mutation rate in the HCV genome, which generates new genotypes and sub genotypes. A mass of efforts have been devoted for the development of an efficient vaccine against HCV. DNA Vaccines, an emerging field of Vaccinology, grasp strong potential to be the most reliable and efficient mode of vaccination in the future. This technology is under investigation currently. Incredibly diverse approaches have been applied as an endeavor to develop a potent DNA vaccine against HCV. The HCV structural genes and the virus like particles have been attempted and so far the results are quite promising in the Lab animals. As there is no proper animal model for HCV infection except chimpanzees, it is very difficult to articulate whether these vaccines will also be pertinent in humans or not. This review will focus on different approaches being used for the development of DNA vaccines, the major tribulations in designing a DNA vaccine against HCV as well as the future prospects for the improvement of under trials DNA vaccines developed against HCV.
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Affiliation(s)
- Sami Ullah
- NUST Center of Virology and Immunology, National University of Science and Technology, Islamabad, Pakistan
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Aljumah AA, Saeed MA, Al Flaiw AI, Al Traif IH, Al Alwan AM, Al Qurashi SH, Al Ghamdi GA, Al Hejaili FF, Al Balwi MA, Al Sayyari AA. Efficacy and safety of treatment of hepatitis C virus infection in renal transplant recipients. World J Gastroenterol 2012; 18:55-63. [PMID: 22228971 PMCID: PMC3251806 DOI: 10.3748/wjg.v18.i1.55] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 04/20/2011] [Accepted: 04/27/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy and safety of combined pegylated interferon and ribavirin therapy in hepatitis C virus (HCV) infection in renal transplant recipients.
METHODS: This is a retrospective chart review of post renal transplant patients who were positive for anti-HCV and HCV-RNA, and who have received treatment with combination of pegylated interferon and ribavirin between October 2003 and December 2008. Only patients with stable graft function and absence of evidence of cirrhosis and who received the therapy for continuous 48 wk were included. Nineteen patients (13 male and 6 female) were identified and included. The patient’s complete blood count, liver and kidney profile, and calculated glomerular filtration rate (GFR) were monitored every 6-8 wk while on treatment. HCV-RNA was tested at 12 wk for early virological response, at 48 wk for end of treatment response (ETR), and then retested at 24, and 48 wk after completion of therapy for sustained virological response (SVR). Liver biopsies were obtained before treatment from all patients and graft kidney biopsies were performed as required.
RESULTS: Of the entire cohort, 9 patients (47.4%) showed an ETR and 8 had SVR (42.1%). Of the 8 patients with abnormal alanine aminotransferase (ALT) levels at baseline, 78.9% had their ALT normalized (including the virological non responders). ALT was normal in all responders at the end of therapy and at 24 wk post therapy (100%). Only one patient (5.3%) developed an increase in creatinine and decline in GFR from baseline towards the end of treatment. This patient’s kidney biopsy revealed borderline rejection. There was no impact on response by HCV-genotype, initial HCV RNA load, age or sex of the patient or duration post transplant before commencement of therapy. All patients tolerated treatment in the same way as non-transplant with no unusual or increased occurrence of side effects.
CONCLUSION: The combination of pegylated interferon and ribavirin is effective in suppressing HCV-RNA, with a low risk of graft rejection or failure in HCV infected renal transplant recipients.
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Piccoli LDZ, Mattos AAD, Coral GP, Mattos AZD, Santos DED. Analysis of the sustained virological response in patients with chronic hepatitis C and liver steatosis. ARQUIVOS DE GASTROENTEROLOGIA 2011; 48:179-85. [PMID: 21952702 DOI: 10.1590/s0004-28032011000300005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Accepted: 01/13/2011] [Indexed: 11/22/2022]
Abstract
CONTEXT Chronic hepatitis C as well as non-alcoholic fatty liver disease are recognized as the main cause of liver disease in Western countries. It is common to see the concomitance of the diseases and the influence of steatosis in the sustained virological response of patients with hepatitis C virus. OBJECTIVE Assess the sustained virological response in chronic hepatitis C patients according to the presence of liver steatosis. METHODS One hundred sixty patients with chronic hepatitis C were retrospectively evaluated. Demographic data such as gender, age, body mass index, presence of diabetes mellitus and systemic arterial hypertension, virus genotype and use of pegylated interferon were analyzed, as was the staging of fibrosis and the presence of steatosis at histology. RESULTS Most patients were male (57.5%), with a mean age of 48 ± 9.7 years. The most frequent genotype observed was 3 (56.9%) and, in the histological evaluation, steatosis was observed in 65% of the patients (104/160). Sustained virological response in patients with steatosis occurred in 38.5%, and in 32.1% in patients without steatosis (P = 0.54). When we analyzed possible factors associated with the presence of steatosis, only body mass index and systemic arterial hypertension revealed a significant association. When the factors that influenced sustained virological response were evaluated in a logistic regression, genotype and use of pegylated interferon proved to be independent factors associated to the response. CONCLUSION In the evaluated patients the presence of liver steatosis did not influence the sustained virological response of patients with chronic hepatitis C treated with interferon and ribavirin.
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Affiliation(s)
- Leonora De Zorzi Piccoli
- Gastroenterology and Hepatology Unit of Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brasil
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D'Heygere F, George C, Van Vlierberghe H, Decaestecker J, Nakad A, Adler M, Delwaide J, Laureys A, Nevens F. Efficacy of interferon-based antiviral therapy in patients with chronic hepatitis C infected with genotype 5: a meta-analysis of two large prospective clinical trials. J Med Virol 2011; 83:815-9. [PMID: 21412790 DOI: 10.1002/jmv.22049] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The characteristics and response rate to pegylated interferon and ribavirin (PEG-INF + RBV) of patients with chronic hepatitis C infected with genotype 5 are poorly documented. A meta-analysis of two large phase III/IV prospective randomized clinical trials conducted in Belgium in patients with chronic hepatitis C (n = 1,073 patients) was performed in order to compare the response to antiviral therapy of hepatitis C virus (HCV) genotype 5 with that of other HCV genotypes. A subset of HCV-1 infected patients selected from within the study database were selected to match the HCV-5 sample for known prognostic factors. In Belgium HCV-5 is responsible for a significant minority of cases of chronic hepatitis C CHC (4.5%) and is characterized by a more advanced age (58.4 years), a high frequency of cirrhosis (27.7%), a specific mode of HCV acquisition, and a particular geographic origin (66.7% of patients from West Flanders). The primary comparative analysis showed that response to treatment with PEG-INF + RBV of HCV-5 is similar to HCV-1 and lower compared to HCV-2/3. The analysis of the matched patient subgroup demonstrates that the HCV-5 "intrinsic sensitivity" to PEG-IFN + RBV therapy is identical to HCV-1, with a sustained virological response of 55% in both groups. In contrast to previous publications, this meta-analysis suggests that HCV-5 response to treatment is closer to HCV-1 than to HCV-2/3 and suggests that in Belgium HCV-5 infection should be treated with the same antiviral regimen as HCV-1.
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Dalagiorgou G, Vassilaki N, Foka P, Boumlic A, Kakkanas A, Kochlios E, Khalili S, Aslanoglou E, Veletza S, Orfanoudakis G, Vassilopoulos D, Hadziyannis SJ, Koskinas J, Mavromara P. High levels of HCV core+1 antibodies in HCV patients with hepatocellular carcinoma. J Gen Virol 2011; 92:1343-1351. [DOI: 10.1099/vir.0.023010-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The core region of the hepatitis C virus (HCV) genome possesses an overlapping ORF that has been shown to encode a protein, known as the alternate reading frame protein (ARFP), F or core+1. The biological role of this protein remains elusive, as it appears to be non-essential for virus replication. However, a number of independent studies have shown that the ARFP/F/core+1 protein elicits humoral and cellular immune responses in HCV-infected individuals and interacts with important cellular proteins. To assess the significance of the core+1 humoral response in HCV-infected patients, we examined the prevalence of anti-core+1 antibodies in sera from patients with hepatocellular carcinoma (HCC) in comparison with chronically HCV-infected individuals without HCC. We produced two HCV core+1 histidine-tagged recombinant proteins for genotypes 1a (aa 11–160) and 1b (aa 11–144), as well as a non-tagged highly purified recombinant core+1/S protein (aa 85–144) of HCV-1b. Using an in-house ELISA, we tested the prevalence of core+1 antibodies in 45 patients with HCC in comparison with 47 chronically HCV-infected patients without HCC and 77 negative-control sera. More than 50 % of the serum samples from HCC patients reacted with all core+1 antigens, whereas <26 % of the sera from the non-HCC HCV-infected individuals tested positive. No core+1-specific reactivity was detected in any of the control samples. In conclusion, the high occurrence of anti-core+1 antibodies in the serum of HCC patients suggests a role for the ARFP/F/core+1 protein in the pathogenesis of HCC.
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Affiliation(s)
- G. Dalagiorgou
- Democritus University of Thrace Medical School, Alexandroupolis, Greece
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - N. Vassilaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - P. Foka
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - A. Boumlic
- University of Strasbourg-CNRS FRE 3211, Oncoprotein group, IREBS, Illkirch, France
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - A. Kakkanas
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - E. Kochlios
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - S. Khalili
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - E. Aslanoglou
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - S. Veletza
- Democritus University of Thrace Medical School, Alexandroupolis, Greece
| | - G. Orfanoudakis
- University of Strasbourg-CNRS FRE 3211, Oncoprotein group, IREBS, Illkirch, France
| | - D. Vassilopoulos
- Academic Department of Medicine, Athens University School of Medicine, Hippokration General Hospital, Athens, Greece
| | - S. J. Hadziyannis
- Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece
| | - J. Koskinas
- Second Department of Internal Medicine, Medical School of Athens, Hippokration General Hospital, Athens, Greece
| | - P. Mavromara
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
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Ashfaq UA, Javed T, Rehman S, Nawaz Z, Riazuddin S. An overview of HCV molecular biology, replication and immune responses. Virol J 2011; 8:161. [PMID: 21477382 PMCID: PMC3086852 DOI: 10.1186/1743-422x-8-161] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 04/11/2011] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) causes acute and chronic hepatitis which can eventually lead to permanent liver damage, hepatocellular carcinoma and death. Currently, there is no vaccine available for prevention of HCV infection due to high degree of strain variation. The current treatment of care, Pegylated interferon α in combination with ribavirin is costly, has significant side effects and fails to cure about half of all infections. In this review, we summarize molecular virology, replication and immune responses against HCV and discussed how HCV escape from adaptive and humoral immune responses. This advance knowledge will be helpful for development of vaccine against HCV and discovery of new medicines both from synthetic chemistry and natural sources.
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Affiliation(s)
- Usman A Ashfaq
- Division of Molecular Medicine, National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
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Abreha T, Woldeamanuel Y, Pietsch C, Maier M, Asrat D, Abebe A, Hailegiorgis B, Aseffa A, Liebert UG. Genotypes and viral load of hepatitis C virus among persons attending a voluntary counseling and testing center in Ethiopia. J Med Virol 2011; 83:776-82. [DOI: 10.1002/jmv.21788] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2010] [Indexed: 12/28/2022]
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Zhang C, Wu N, Liu J, Ge Q, Huang Y, Ren Q, Feng Q, He G. HCV subtype characterization among injection drug users: implication for a crucial role of Zhenjiang in HCV transmission in China. PLoS One 2011; 6:e16817. [PMID: 21304823 PMCID: PMC3033423 DOI: 10.1371/journal.pone.0016817] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 01/11/2011] [Indexed: 01/23/2023] Open
Abstract
Background HCV transmission is closely associated with drug-trafficking routes in China. However, the transmission route of HCV in Eastern China remains unclear. Here, we investigate the role of Zhenjiang city of Jiangsu province, an important transportation hub linking Shanghai with other regions of China, in HCV transmission. Methodology/Principal Findings A total of 141 whole blood samples were collected from injection drug users (IDUs) in Zhenjiang and then tested for HCV infection. Of them, 115 HCV positive plasmas were subjected to RNA extraction, RT-PCR amplification, and sequencing. The subtype characterization and the evolutionary origin of HCV strains circulating in Zhenjiang were determined using polygenetic or phylogeographic analyses. Seven HCV subtypes 1b, 2a, 3a, 3b, 6a, 6e and 6n were detected among Zhenjiang IDUs, showing a complex HCV epidemic. The most predominant subtypes were 3a (38%) and 1b (26.8%). Among these subtypes, subtypes 3b, 6n and 6e originated from Southwestern China (i.e., Yunnan and/or Guangxi), subtypes 2a and 6a from Southern China (i.e., Guangdong), subtype 1b from Central (i.e., Henan) and Northwestern (i.e., Xinjiang) China, and subtype 3a from Southwestern (i.e., Yunnan) and Northwestern (i.e., Xinjiang) China. From Zhenjiang, subtypes 1b and 2a were further spread to Eastern (i.e., Shanghai) and Northern (i.e., Beijing) China, respectively. Conclusions/Significance The mixing of seven HCV subtypes in Zhenjiang from all quarters of China indicates that as an important middle station, Zhenjiang plays a crucial role in HCV transmission, just as it is important in population migration between other regions of China and Eastern China.
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Affiliation(s)
- Chiyu Zhang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China.
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2011:811-828.e5. [DOI: 10.1016/b978-1-4377-0774-8.10075-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Bertino G, Ardiri A, Boemi PM, Calvagno GS, Ruggeri IM, Speranza A, Santonocito MM, Ierna D, Bruno CM, Valenti M, Boemi R, Naimo S, Neri S. Epoetin alpha improves the response to antiviral treatment in HCV-related chronic hepatitis. Eur J Clin Pharmacol 2010; 66:1055-63. [PMID: 20652232 DOI: 10.1007/s00228-010-0868-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 07/06/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND The conventional antiviral treatment of chronic hepatitis related to hepatitis C virus (HCV) often leads to anemia. In this case, it is necessary to reduce ribavirin dose or stop treatment, thus reducing the rate of sustained virological response. AIM We investigated whether epoetin alpha administration improves treatment adherence and leads to higher percentage of response at the end of therapy and sustained virological response. METHODS Two hundred and fourteen individuals with genotype 1b HCV-related chronic hepatitis underwent treatment with pegylated (peg)-interferon alpha-2A 180 μg once weekly and ribavirin 1,000-1,200 mg/day; 174 were responders. Forty individuals completed treatment with no hemoglobin reduction; 134 developed anemia during therapy. Anemic responders were distributed randomly into two groups: group 1 continued therapy with epoetin alpha addiction; group 2 continued antiviral therapy with ribavirin reduction only. RESULTS Patients in group 1 achieved better control of hemoglobin levels (13.8 ± 1.2 g/dl at the end of therapy) than those in group 2 (11.5 ± 0.8 g/dl). Sustained virological response was 59.7% in group 1 compared with 34.4% in group 2 (p<0.01). CONCLUSIONS In patients with 1b HCV-related chronic hepatitis who develop anemia during antiviral treatment, administration of epoetin alpha increases hemoglobin levels and the end-of-treatment rate and sustains virological response by improving treatment adherence.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Internal Medicine and Systemic Diseases, University of Catania, S. Marta Hospital, Via Gesualdo Clementi, 36, 95124 Catania, Italy.
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Abstract
Hepatitis C (HCV) is the disease that has affected around 200 million people globally. HCV is a life threatening human pathogen, not only because of its high prevalence and worldwide burden but also because of the potentially serious complications of persistent HCV infection. Chronicity of the disease leads to cirrhosis, hepatocellular carcinoma and end-stage liver disease. HCV positive hepatocytes vary between less than 5% and up to 100%, indicating the high rate of replication of viral RNA. HCV has a very high mutational rate that enables it to escape the immune system. Viral diversity has two levels; the genotypes and Quasiaspecies. Major HCV genotypes constitute genotype 1, 2, 3, 4, 5 and 6 while more than 50 subtypes are known. All HCV genotypes have their particular patterns of geographical distribution and a slight drift in viral population has been observed in some parts of the globe.
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Affiliation(s)
- Nazish Bostan
- Department of Biological Sciences, Quaid-i-Azam University, Islamabad-45320, Pakistan
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Zarkesh-Esfahani SH, Kardi MT, Edalati M. Hepatitis C virus genotype frequency in Isfahan province of Iran: a descriptive cross-sectional study. Virol J 2010; 7:69. [PMID: 20331907 PMCID: PMC2852391 DOI: 10.1186/1743-422x-7-69] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 03/24/2010] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV). The hepatitis C virus is a small, enveloped, single-stranded, positive sense RNA virus with a large genetic heterogeneity. Isolates have been classified into at least eleven major genotypes, based on a nucleotide sequence divergence of 30-35%. Genotypes 1, 2 and 3 circulate around the world, while other genotypes are mainly restricted to determined geographical areas. Genotype determination of HCV is clinically valuable as it provides important information which can be used to determine the type and duration of therapy and to predict the outcome of the disease. RESULTS Plasma samples were collected from ninety seven HCV RNA positive patients admitted to two large medical laboratory centers in Isfahan province (Iran) from the years 2007 to 2009. Samples from patients were subjected to HCV genotype determination using a PCR based genotyping kit. The frequency of HCV genotypes was determined as follows: genotype 3a (61.2%), genotype 1a (29.5%), genotype 1b (5.1%), genotype 2 (2%) and mixed genotypes of 1a+3a (2%). CONCLUSION Genotype 3a is the most frequent followed by the genotype 1a, genotype 1b and genotype 2 in Isfahan province, Iran.
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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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Bhogal RH, Afford SC. Immune Cell Communication and Signaling Systems in Liver Disease. SIGNALING PATHWAYS IN LIVER DISEASES 2010:117-146. [DOI: 10.1007/978-3-642-00150-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Fishman SL, Branch AD. The quasispecies nature and biological implications of the hepatitis C virus. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2009; 9:1158-67. [PMID: 19666142 PMCID: PMC2790008 DOI: 10.1016/j.meegid.2009.07.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Revised: 07/24/2009] [Accepted: 07/31/2009] [Indexed: 12/18/2022]
Abstract
Many RNA viruses exist as a cloud of closely related sequence variants called a quasispecies, rather than as a population of identical clones. In this article, we explain the quasispecies nature of RNA viral genomes, and briefly review the principles of quasispecies dynamics and the differences with classical population genetics. We then discuss the current methods for quasispecies analysis and conclude with the biological implications of this phenomenon, focusing on the hepatitis C virus.
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Affiliation(s)
- Sarah L Fishman
- Mount Sinai School of Medicine, Department of Medicine, Division of Liver Diseases. 1425 Madison Ave, Box 11-20 New York, NY 10029, +1 212 659 8371 Tel, +1 212 348 3571 Fax,
| | - Andrea D Branch
- Mount Sinai School of Medicine, Department of Medicine, Division of Liver Diseases. 1425 Madison Ave, Box 11-20 New York, NY 10029, +1 212 659 8371 Tel, +1 212 348 3571 Fax,
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Abstract
This review describes work conducted largely in my laboratory at the Chiron Corporation between 1982 and 1989 that led to the identification of the hepatitis C virus (HCV). Key colleagues included Dr. Qui-Lim Choo in my laboratory and Dr. George Kuo also of Chiron as well as my collaborator Dr. Daniel Bradley at the CDC who provided many biological samples from the NANBH chimpanzee model. Numerous molecular approaches were explored including the screening of tens of millions of bacterial cDNA clones derived from these materials. While this early genomics approach resulted in the identification of many host gene activities associated with NANBH, no genes of proven infectious etiology could be identified. A separate avenue of our research led to the molecular characterization of the complete hepatitis delta viral genome but unfortunately, this could not be used as a molecular handle for HCV. Largely following input from Dr. Kuo, I initiated a blind cDNA immunoscreening approach involving the large-scale screening of bacterial proteomic cDNA libraries derived from NANBH-infectious chimpanzee materials (prior to the development of PCR technology) using sera from NANBH patients as a presumptive source of viral antibodies. Eventually, this novel approach to identifying agents of infectious etiology led to the isolation of a single small cDNA clone that was proven to be derived from the HCV genome using various molecular and serological criteria. This discovery has facilitated the development of effective diagnostics, blood screening tests and the elucidation of promising drug and vaccine targets to control this global pathogen.
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Costi C, da Silva CMD, Da Fré NN, Grandi T, Hamester FI, Zaha A, Niel C, Rossetti MLR. Colorimetric microwell plate reverse-hybridization assay for detection and genotyping of hepatitis C virus. J Virol Methods 2009; 162:75-80. [PMID: 19643142 DOI: 10.1016/j.jviromet.2009.07.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 07/13/2009] [Accepted: 07/21/2009] [Indexed: 01/06/2023]
Abstract
This study describes a colorimetric method for detecting and genotyping hepatitis C virus (HCV) in which four different oligonucleotide probes are fixed onto microwell plates and hybridized separately with biotinylated PCR amplification products derived from clinical samples. The first probe capable of hybridizing with all seven known HCV genotypes was used for overall detection, and the remaining probes were used to recognize specifically genotypes 1-3. When combined with an improved silica-based RNA extraction method, the sensitivity of the test was 50 IU/mL. Eighty-five of the 86 samples analyzed (98.8%) yielded results in agreement with reference detection methods. The remaining sample was HCV-RNA positive in the COBAS Amplicor qualitative assay, but was negative using the reverse-hybridization method. The usefulness of the new genotyping test was confirmed by comparison with direct sequencing of PCR products: 98% of samples tested (54/55) were in agreement using the two methods (21, 7 and 27 from genotypes 1-3, respectively). The single discrepancy might have been due to a mixed HCV infection. The new method is an alternative to the use of commercially available genotyping kits and should be particularly convenient in developing countries where genotypes 1-3 represent a high proportion of HCV isolates.
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Affiliation(s)
- Cintia Costi
- Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde (CDCT/FEPPS), Porto Alegre, Brazil
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Iro M, Witteveldt J, Angus AGN, Woerz I, Kaul A, Bartenschlager R, Patel AH. A reporter cell line for rapid and sensitive evaluation of hepatitis C virus infectivity and replication. Antiviral Res 2009; 83:148-55. [PMID: 19397930 DOI: 10.1016/j.antiviral.2009.04.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2008] [Revised: 04/06/2009] [Accepted: 04/17/2009] [Indexed: 01/23/2023]
Abstract
The human pathogen hepatitis C virus (HCV) is associated with chronic liver disease. The recent development of the cell culture infectious HCV (HCVcc) system has opened up avenues for detailed studies on the life cycle of the virus and its interaction with the host cell. Current methods to quantitate virus infectivity in cell culture are time-consuming and labor-intensive. This study describes the generation of a cell-based secreted alkaline phosphatase (SEAP) reporter assay to facilitate in vitro studies of HCV infection and replication. This assay is based on a novel reporter cell line stably expressing the enhanced green fluorescent protein (EGFP) fused in-frame to the secreted alkaline phosphatase via a recognition sequence of the viral NS3/4A serine protease. The SEAP reporter from a similar construct has previously been shown to be released from the fusion protein and be secreted into the extracellular culture medium following cleavage by the viral NS3/4A protease. The reporter cell line enabled rapid and sensitive quantification of HCV infection and viral replication in cell culture. The utility of this system for investigating virus entry, and for high throughput screening of entry inhibitors and other antiviral compounds was demonstrated using several inter- and intra-genotypic chimeras of HCV.
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Affiliation(s)
- Michaela Iro
- MRC Virology Unit, Institute of Virology, University of Glasgow, Glasgow, United Kingdom
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Al-Khurri LE, Al-Khafaji KR, Al-Salihi SA, Alwaysi SAA, Al-Akayshi RJ. Serum HCV-RNA levels in patients with chronic hepatitis C: Correlation with histological features. Arab J Gastroenterol 2009; 10:10-3. [PMID: 24842130 DOI: 10.1016/j.ajg.2009.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND STUDY AIMS Liver disease in chronic hepatitis C virus (HCV) infection ranges from minimal lesion to liver cirrhosis and sometimes eventually evolving hepatocellular carcinoma. Whether and how HCV determines the different clinical and histological manifestation of the disease is not fully understood. It has not been clearly elucidated whether the extent of liver injury induced by HCV is influenced mainly by direct cytopathic damage or by an immune-mediated response against HCV-infected hepatocytes. The aim of this study is to verify whether the amount of virus in individual patient's serum could be related to the severity of liver injury. PATIENTS AND METHODS This study was carried out in the Gastroenterology and Hepatology Teaching Hospital, Medical City, Baghdad. Serum levels of HCV-RNA were measured in 27 patients with chronic HCV using b-DNA assay. Core liver biopsies of the patients were evaluated according to Ishak histological activity index system. RESULTS The serum HCV RNA concentrations in the patients ranged from 3.2×10(3) to 1.2×10(7)copies/ml. In all patients no correlation was observed between the variable levels of viraemia and the age of the patients. Furthermore no correlations were observed between the serum HCV RNA concentrations and the biochemical liver function test levels: Total serum bilirubin, AST, ALT, and alkaline phosphatase. Histologically; patients were categorized into four subgroups: four patients (14.8%) had minimal activity, 17 patients (63%) had mild activity, and six patients (22.2%) had moderate activity. No significant correlation was found between viraemic levels and these histological findings or their individual components: Interface hepatitis, confluent necrosis, intralobular liver cell necrosis and portal inflammation. According to the stage of the fibrosis, the patients were categorized into seven subgroups: one patient (3.7%) with stage zero, seven patients with stage one (25.9%), four patients with stage two (14.9%), eight patients with stage three (29.6%), three patients with stage four (11.1%), two patients with stage five (7.4%), and two patients in cirrhotic stage six (7.4%). There was no correlation between the serum HCV RNA concentration and the stage of fibrosis. Hepatic steatosis was observed in 16/27 patients. It was mild in nine patients, moderate in five patients, and severe in two patients. Correlation has not been observed between the serum HCV RNA viraemic level and the severity of steatosis. CONCLUSION Serum HCV-RNA level does not determine the degree of hepatic injury precisely and liver biopsy is necessary to accurately evaluate the extent of liver damage.
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Affiliation(s)
- Luay E Al-Khurri
- Pathology Department, College of Medicine, Baghdad University, Baghdad, Iraq
| | - Khitam R Al-Khafaji
- Pathology Department, College of Medicine, Baghdad University, Baghdad, Iraq
| | - Suhair A Al-Salihi
- Laboratory Department, Gastroenterology and Hepatology Teaching Hospital, Medical City, Baghdad, Iraq.
| | - Safa A A Alwaysi
- Laboratory Department, Gastroenterology and Hepatology Teaching Hospital, Medical City, Baghdad, Iraq
| | - Raghad J Al-Akayshi
- Medical Department, Gastroenterology and Hepatology Teaching Hospital, Medical City, Baghdad, Iraq
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