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• W2000587801 abstract "Infection with hepatitis C virus (HCV) genotypes 4–6 (with the previously named genotypes 7–9 included as subtypes of genotype 6) is distributed and studied less widely than genotypes 1–3. However, genotypes 4–6 are very common in geographic areas where chronic hepatitis C is highly prevalent. In fact, the majority (87%) of the 169.7 million HCV-infected individuals worldwide are from western Pacific countries (62.2 million), southeast Asia (32.3 million), Africa (31.9 million), and eastern Mediterranean countries (21.3 million). It is among this large population outside of the Americas and Europe that these less well known genotypes are found: genotype 4 in Egypt and Africa, genotype 5 in South Africa, and genotype 6 in southeast Asia. The existing literature, although limited, suggests that patients with chronic hepatitis C genotypes 4–6 may exhibit different clinical courses and treatment outcomes. Ethnicity-related factors may contribute to the presence of more advanced disease in patients with genotype 4, who also tend to have a poor response to interferon-based therapy. HCV genotype 5 appears to be an easy-to-treat virus with response rates similar to those of genotypes 2 and 3 after a 48-week course of therapy. Response to treatment in patients with HCV genotype 6 may be at an intermediate level between that seen with genotype 1 and genotype 2 or 3. The optimal duration of treatment (24 vs 48 wk) for HCV genotype 6 is unclear and currently is under investigation. Infection with hepatitis C virus (HCV) genotypes 4–6 (with the previously named genotypes 7–9 included as subtypes of genotype 6) is distributed and studied less widely than genotypes 1–3. However, genotypes 4–6 are very common in geographic areas where chronic hepatitis C is highly prevalent. In fact, the majority (87%) of the 169.7 million HCV-infected individuals worldwide are from western Pacific countries (62.2 million), southeast Asia (32.3 million), Africa (31.9 million), and eastern Mediterranean countries (21.3 million). It is among this large population outside of the Americas and Europe that these less well known genotypes are found: genotype 4 in Egypt and Africa, genotype 5 in South Africa, and genotype 6 in southeast Asia. The existing literature, although limited, suggests that patients with chronic hepatitis C genotypes 4–6 may exhibit different clinical courses and treatment outcomes. Ethnicity-related factors may contribute to the presence of more advanced disease in patients with genotype 4, who also tend to have a poor response to interferon-based therapy. HCV genotype 5 appears to be an easy-to-treat virus with response rates similar to those of genotypes 2 and 3 after a 48-week course of therapy. Response to treatment in patients with HCV genotype 6 may be at an intermediate level between that seen with genotype 1 and genotype 2 or 3. The optimal duration of treatment (24 vs 48 wk) for HCV genotype 6 is unclear and currently is under investigation. Globally, infection with hepatitis C virus (HCV) genotypes 4–6 represents a large proportion of patients with chronic hepatitis C.1Alter M.J. Kruszon-Moran D. Nainan O.V. et al.The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.N Engl J Med. 1999; 341: 556-562Crossref PubMed Scopus (2419) Google Scholar, 2Simmonds P. Viral heterogeneity of the hepatitis C virus.J Hepatol. 1999; 31: 54-60Abstract Full Text PDF PubMed Google Scholar, 3Farci P. Purcell R.H. Clinical significance of hepatitis C virus genotypes and quasispecies.Semin Liver Dis. 2000; 20: 103-126PubMed Google Scholar In the United States, knowledge regarding these genotypes is pertinent for providers who take care of immigrants from corresponding endemic areas. This synopsis reviews salient points to assist practitioners in providing accurate diagnosis and appropriate treatment for HCV-infected patients with these less well known genotypes. Although HCV genotypes 4 and 5 can be diagnosed reliably by most commercially available assays for HCV genotyping (Table 1), the diagnosis of certain subtypes of genotype 6 (the so-called novel genotypes 7–9) can be a challenge using similar diagnostic assays. Genotypes 7–9 are related closely to genotype 6 and recently have been reclassified as subtypes of genotype 6 by the Los Alamos National Laboratories (Table 2).4Los Alamos National Laboratories. HCV nomenclature. Available at: www.hcv.lanl.gov/content/hcv-db/classification.genotable. Last updated: September 7, 2004 Accessed: January 14, 2005.Google Scholar HCV genotypes 7–9 share significant homology with genotype 1 in the highly conserved 5′ untranslated regions of the HCV genome (Figure 1) and often can be mistyped as genotype 1, 1a, or 1b if the line-probe assay (INNO-LiPA HCV II; Innogenetics, Ghent, Belgium), one of the most commonly available commercial assays, is used to determine HCV genotype.5Dev A.T. McCaw R. Sundararajan V. et al.Southeast Asian patients with chronic hepatitis C the impact of novel genotypes and race on treatment outcome.Hepatology. 2002; 36: 1259-1265Crossref PubMed Scopus (84) Google Scholar, 6Pawlotsky J.M. Use and interpretation of virological tests for hepatitis C.Hepatology. 2002; 36: S65-S73Crossref PubMed Google Scholar Therefore, the gold standard of HCV genotype determination, which is to sequence parts of the E1 or NS5B regions of the HCV genome directly,6Pawlotsky J.M. Use and interpretation of virological tests for hepatitis C.Hepatology. 2002; 36: S65-S73Crossref PubMed Google Scholar should be considered in patients from areas with a high prevalence of HCV genotypes 7–9, or subtypes of genotype 6.Table 1Commercially Available Assays for HCV GenotypingTest assaysManufacturersMurex HCV serotyping 1–3 and 1–6 assays (serotyping)aSerotyping using type-specific antibodies with a competitive enzyme immunoassay.Murex Diagnostics, Dartfort, United KingdomGen-ETI-K DEIA (serotyping)aSerotyping using type-specific antibodies with a competitive enzyme immunoassay.Sorin Biomedica, Saluggia, ItalyTruGene HCV 5′NC (direct sequence analysis)Visible Genetics, Toronto, Ontario, CanadaINNO-LiPA HCV I (line-probe assay)bLine-probe assay using reverse hybridization to genotype-specific oligonucleotide probes.Innogenetics, Zwijnaarde, BelgiumINNO-LiPA HCV II (line-probe assay)bLine-probe assay using reverse hybridization to genotype-specific oligonucleotide probes.Innogenetics, Ghent, Belgiuma Serotyping using type-specific antibodies with a competitive enzyme immunoassay.b Line-probe assay using reverse hybridization to genotype-specific oligonucleotide probes. Open table in a new tab Table 2Reclassification of HCV Novel Genotypes 7–9, and 11 (Los Alamos National Laboratories)Old designationNew designation7a6e7b6d7c6f7d6c8a6l8b6k9a6h9b6i9c6j11a6gData from www.hcv.lanl.gov/content/hcv-db/classification.genotable.4Los Alamos National Laboratories. HCV nomenclature. Available at: www.hcv.lanl.gov/content/hcv-db/classification.genotable. Last updated: September 7, 2004 Accessed: January 14, 2005.Google Scholar Open table in a new tab Data from www.hcv.lanl.gov/content/hcv-db/classification.genotable.4Los Alamos National Laboratories. HCV nomenclature. Available at: www.hcv.lanl.gov/content/hcv-db/classification.genotable. Last updated: September 7, 2004 Accessed: January 14, 2005.Google Scholar HCV genotype 4 is encountered throughout Africa and eastern Mediterranean countries, and usually among immigrants or indigenous injection drug users in North America and Europe.7Ray S.C. Arthur R.R. Carella A. et al.Genetic epidemiology of hepatitis C virus throughout Egypt.J Infect Dis. 2000; 182: 698-707Crossref PubMed Scopus (310) Google Scholar, 8Ramia S. Koussa S. Taher A. et al.Hepatitis-C-virus genotypes and hepatitis-G-virus infection in Lebanese thalassaemics.Ann Trop Med Parasitol. 2002; 96: 197-202Crossref PubMed Scopus (40) Google Scholar, 9Abdulkarim A.S. Zein N.N. Germer J.J. et al.Hepatitis C virus genotypes and hepatitis G virus in hemodialysis patients from Syria identification of two novel hepatitis C virus subtypes.Am J Trop Med Hyg. 1998; 59: 571-576PubMed Google Scholar, 10Shobokshi O.A. Serebour F.E. Skakni L. et al.Hepatitis C genotypes and subtypes in Saudi Arabia.J Med Virol. 1999; 58: 44-48Crossref PubMed Scopus (81) Google Scholar, 11Xu L.Z. Larzul D. Delaporte E. et al.Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon).J Gen Virol. 1994; 75: 2393-2398Crossref PubMed Scopus (94) Google Scholar, 12Argentini C. Dettori S. Villano U. et al.Molecular characterisation of HCV genotype 4 isolates circulating in Italy.J Med Virol. 2000; 62: 84-90Crossref PubMed Scopus (27) Google Scholar, 13Oni A.O. Harrison T.J. Genotypes of hepatitis C virus in Nigeria.J Med Virol. 1996; 49: 178-186Crossref PubMed Google Scholar, 14Lyra A.C. Ramrakhiani S. Bacon B.R. et al.Infection with hepatitis C virus genotype 4 in the United States.J Clin Gastroenterol. 2004; 38: 68-71Crossref PubMed Scopus (38) Google Scholar, 15Njouom R. Pasquier C. Ayouba A. et al.High rate of hepatitis C virus infection and predominance of genotype 4 among elderly inhabitants of a remote village of the rain forest of South Cameroon.J Med Virol. 2003; 71: 219-225Crossref PubMed Scopus (50) Google Scholar, 16Matera G. Lamberti A. Quirino A. et al.Changes in the prevalence of hepatitis C virus (HCV) genotype 4 in Calabria, Southern Italy.Diagn Microbiol Infect Dis. 2002; 42: 169-173Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 17Sanchez-Quijano A. Abad M.A. Torronteras R. et al.Unexpected high prevalence of hepatitis C virus genotype 4 in Southern Spain.J Hepatol. 1997; 27: 25-29Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 18Nicot F. Legrand-Abravanel F. Sandres-Saune K. et al.Heterogeneity of hepatitis C virus genotype 4 strains circulating in south-western France.J Gen Virol. 2005; 86: 107-114Crossref PubMed Scopus (70) Google Scholar Egypt has the highest HCV genotype 4 prevalence of 91% according to a survey of 122 HCV-infected patients from 15 regions of the country.7Ray S.C. Arthur R.R. Carella A. et al.Genetic epidemiology of hepatitis C virus throughout Egypt.J Infect Dis. 2000; 182: 698-707Crossref PubMed Scopus (310) Google Scholar Saudi Arabia probably has the second highest HCV genotype 4 prevalence (60%).10Shobokshi O.A. Serebour F.E. Skakni L. et al.Hepatitis C genotypes and subtypes in Saudi Arabia.J Med Virol. 1999; 58: 44-48Crossref PubMed Scopus (81) Google Scholar The prevalence for HCV genotype 4 varies between 11% and 75% in central Africa based on mostly small reports from various locations from this area.11Xu L.Z. Larzul D. Delaporte E. et al.Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon).J Gen Virol. 1994; 75: 2393-2398Crossref PubMed Scopus (94) Google Scholar, 13Oni A.O. Harrison T.J. Genotypes of hepatitis C virus in Nigeria.J Med Virol. 1996; 49: 178-186Crossref PubMed Google Scholar, 15Njouom R. Pasquier C. Ayouba A. et al.High rate of hepatitis C virus infection and predominance of genotype 4 among elderly inhabitants of a remote village of the rain forest of South Cameroon.J Med Virol. 2003; 71: 219-225Crossref PubMed Scopus (50) Google Scholar More recently, HCV genotype 4 also has been reported from the Caribbean region and in India.19Martial J. Morice Y. Abel S. et al.Hepatitis C virus (HCV) genotypes in the Caribbean island of Martinique evidence for a large radiation of HCV-2 and for a recent introduction from Europe of HCV-4.J Clin Microbiol. 2004; 42: 784-791Crossref PubMed Scopus (44) Google Scholar, 20Raghuraman S. Abraham P. Sridharan G. et al.HCV genotype 4—an emerging threat as a cause of chronic liver disease in Indian (south) patients.J Clin Virol. 2004; 31: 253-258Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 21Singh S. Malhotra V. Sarin S.K. Distribution of hepatitis C virus genotypes in patients with chronic hepatitis C infection in India.Indian J Med Res. 2004; 119: 145-148PubMed Google Scholar In India, the prevalence of HCV genotype 4 was 6.2% based on data abstracted from 2 studies (total n = 161).20Raghuraman S. Abraham P. Sridharan G. et al.HCV genotype 4—an emerging threat as a cause of chronic liver disease in Indian (south) patients.J Clin Virol. 2004; 31: 253-258Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 21Singh S. Malhotra V. Sarin S.K. Distribution of hepatitis C virus genotypes in patients with chronic hepatitis C infection in India.Indian J Med Res. 2004; 119: 145-148PubMed Google Scholar In Western countries, HCV genotype 4 usually is confined to 2 distinct populations: immigrants from endemic areas and native injection drug users.14Lyra A.C. Ramrakhiani S. Bacon B.R. et al.Infection with hepatitis C virus genotype 4 in the United States.J Clin Gastroenterol. 2004; 38: 68-71Crossref PubMed Scopus (38) Google Scholar, 17Sanchez-Quijano A. Abad M.A. Torronteras R. et al.Unexpected high prevalence of hepatitis C virus genotype 4 in Southern Spain.J Hepatol. 1997; 27: 25-29Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 18Nicot F. Legrand-Abravanel F. Sandres-Saune K. et al.Heterogeneity of hepatitis C virus genotype 4 strains circulating in south-western France.J Gen Virol. 2005; 86: 107-114Crossref PubMed Scopus (70) Google Scholar, 22Schroter M. Zollner B. Schafer P. et al.Epidemiological dynamics of hepatitis C virus among 747 German individuals new subtypes on the advance.J Clin Microbiol. 2002; 40: 1866-1868Crossref PubMed Scopus (59) Google Scholar, 23van Asten L. Verhaest I. Lamzira S. et al.Spread of hepatitis C virus among European injection drug users infected with HIV a phylogenetic analysis.J Infect Dis. 2004; 189: 292-302Crossref PubMed Scopus (119) Google Scholar The prevalence of HCV genotype 4 in Europe generally is less than 5%, although it can be significantly higher in some populations in southern France and Italy.12Argentini C. Dettori S. Villano U. et al.Molecular characterisation of HCV genotype 4 isolates circulating in Italy.J Med Virol. 2000; 62: 84-90Crossref PubMed Scopus (27) Google Scholar, 22Schroter M. Zollner B. Schafer P. et al.Epidemiological dynamics of hepatitis C virus among 747 German individuals new subtypes on the advance.J Clin Microbiol. 2002; 40: 1866-1868Crossref PubMed Scopus (59) Google Scholar Patients with HCV genotype 4 respond poorly to antiviral therapy with conventional interferon (IFN) monotherapy (a sustained virologic response [SVR] rate of approximately 10%) or in combination with ribavirin (SVR of 10%–40%).24Remy A.J. Verdier E. Perney P. et al.Route of infection, liver histology and response to interferon in patients with chronic hepatitis caused by genotype 4 HCV infection in a Western country.J Hepatol. 1998; 29: 169Abstract Full Text PDF PubMed Scopus (16) Google Scholar, 25Zylberberg H. Chaix M.L. Brechot C. Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha.Ann Intern Med. 2000; 132: 845-846Crossref PubMed Scopus (62) Google Scholar, 26el-Zayadi A. Selim O. Haddad S. et al.Combination treatment of interferon alpha-2b and ribavirin in comparison to interferon monotherapy in treatment of chronic hepatitis C genotype 4 patients.Ital J Gastroenterol Hepatol. 1999; 31: 472-475PubMed Google Scholar, 27Koshy A. Marcellin P. Martinot M. et al.Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis.Liver. 2000; 20: 335-339Crossref PubMed Scopus (41) Google Scholar, 28Koshy A. Madda J.P. Marcellin P. et al.Treatment of hepatitis C virus genotype 4-related cirrhosis ribavirin and interferon combination compared with interferon alone.J Clin Gastroenterol. 2002; 35: 82-85Crossref PubMed Scopus (37) Google Scholar, 29Shiha G. Salem S. Interferon alone or in combination with ribavirin for the treatment of chronic hepatitis C genotype IV.J Hepatol. 2002; 36: 129Abstract Full Text PDF Google Scholar Few published studies and a number of abstracts presented at various international meetings in the past 3 years report much more encouraging results for patients treated with combination therapy with peginterferon and ribavirin (PEG IFN + RBV) for 48 weeks (SVR of 60%–80%) (Table 3).30Diago M. Hadziayannus S. Bodenheimer Jr, H. et al.Optimized virological response in genotype 4 chronic hepatitis C patients treated with peginterferon alfa-2a (PEGASYS) in combination with ribavirin (RBV).Hepatology. 2002; 36: 364AGoogle Scholar, 31Thakeb F. Omar M. Bilharz T. et al.Randomized controlled trial of peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus-genotype 4 among Egyptian patients.Hepatology. 2003; 38: 278ACrossref Google Scholar, 32Esmat G. Mohamed M.K. Hamid M.A. et al.The impact of steatosis on baseline characteristic and end of treatment response for chronic hepatitis (C) genotype 4 patients treated with interferon.J Hepatol. 2003; 38: 139Abstract Full Text PDF Google Scholar, 33Shobokshi O.A. Serebour F.E. Skakni L. et al.Efficacy of pegylated (40 KDA) IFN alfa-2a (PEGASYS) plus ribavirin in the treatment of hepatitis C genotype 4 chronic active patients in Saudi Arabia.J Hepatol. 2002; 36: 129Abstract Full Text PDF Google Scholar, 34Hasan F. Asker H. Al-Khaldi J. et al.Pegylated interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C genotype 4.Hepatology. 2003; 38: 629ACrossref PubMed Google Scholar, 35Hasan F. Asker H. Al-Khaldi J. et al.Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4.Am J Gastroenterol. 2004; 99: 1733-1737Crossref PubMed Scopus (109) Google Scholar, 36Alfaleh F.Z. Hadad Q. Khuroo M.S. et al.Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.Liver Int. 2004; 24: 568-574Crossref PubMed Scopus (71) Google ScholarTable 3Response to PEG IFN and RBV Combination Therapy for Chronic Hepatitis C With Genotype 4StudyTherapyDuration (wk)RCTaRandomized controlled trial.Intention-to-treat analysisNSVRPDiago et al,30Diago M. Hadziayannus S. Bodenheimer Jr, H. et al.Optimized virological response in genotype 4 chronic hepatitis C patients treated with peginterferon alfa-2a (PEGASYS) in combination with ribavirin (RBV).Hepatology. 2002; 36: 364AGoogle Scholar 2002, Europe and the United StatesPEG IFN alfa-2a 180 mcg + RBV 1–1.2 g48NoNRbNot reported.2479%—PEG IFN alfa-2a + RBV .848NR63%PEG IFN alfa-2a +RBV 1–1.2241367%Thakeb et al,31Thakeb F. Omar M. Bilharz T. et al.Randomized controlled trial of peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus-genotype 4 among Egyptian patients.Hepatology. 2003; 38: 278ACrossref Google Scholar 2003, EgyptPEG IFN alfa-2a 180 mcg + RBV 1–1.2 g48YesYes5168.6%<.001IFN 3 MU + RBV 1–1.2 g484916.4%Esmat et al,32Esmat G. Mohamed M.K. Hamid M.A. et al.The impact of steatosis on baseline characteristic and end of treatment response for chronic hepatitis (C) genotype 4 patients treated with interferon.J Hepatol. 2003; 38: 139Abstract Full Text PDF Google Scholar 2003, EgyptPEG IFN alfa-2b 100 mcg + RBV .8–1.0 g48YesYes4040%NScNot significant.IFN 3 MU + RBV .8–1.0 g483839%Shobokshi et al,33Shobokshi O.A. Serebour F.E. Skakni L. et al.Efficacy of pegylated (40 KDA) IFN alfa-2a (PEGASYS) plus ribavirin in the treatment of hepatitis C genotype 4 chronic active patients in Saudi Arabia.J Hepatol. 2002; 36: 129Abstract Full Text PDF Google Scholar 2003, Saudi ArabiaPEG IFN alfa-2a 180 mcg + RBV .8 g48YesNR6050%<.01PEG IFN alfa-2a 180 mcg486025%IFN 4.5 MU + RBV .8 g486030%Alfaleh et al,36Alfaleh F.Z. Hadad Q. Khuroo M.S. et al.Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.Liver Int. 2004; 24: 568-574Crossref PubMed Scopus (71) Google Scholar 2004, Saudi ArabiaPEG IFN alfa-2b 100 mcg + RBV .8g48YesYes2842.9%.43IFN 3 MU + RBV .8g483132.3%Hasan et al,35Hasan F. Asker H. Al-Khaldi J. et al.Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4.Am J Gastroenterol. 2004; 99: 1733-1737Crossref PubMed Scopus (109) Google Scholar 2004, KuwaitPEG IFN alfa-2b 1.5 mcg/kg + RBV 1–1.2g48NoYes6668%—a Randomized controlled trial.b Not reported.c Not significant. Open table in a new tab Our knowledge of the natural history of HCV genotype 4 is poor (and essentially nonexistent for genotypes 5 and 6). Limited observational studies report that patients with HCV genotype 4 may have higher rates of liver-related morbidity, liver transplantation, and liver-related death; however, these studies failed to show that genotype 4 is an independent predictor of such clinical outcomes on multivariate analysis.37Gane E.J. Portmann B.C. Naoumov N.V. et al.Long-term outcome of hepatitis C infection after liver transplantation.N Engl J Med. 1996; 334: 815-820Crossref PubMed Scopus (936) Google Scholar, 38Zekry A. Whiting P. Crawford D.H. et al.Liver transplantation for HCV-associated liver cirrhosis predictors of outcomes in a population with significant genotype 3 and 4 distribution.Liver Transpl. 2003; 9: 339-347Crossref PubMed Scopus (60) Google Scholar In the case of posttransplant patients with HCV genotype 4, poorer outcomes with higher rates of complications (graft-related complications with cholestatic hepatitis, recurrent hepatitis C with cirrhosis, and vascular complications) and varying short and medium survival times also have been reported.38Zekry A. Whiting P. Crawford D.H. et al.Liver transplantation for HCV-associated liver cirrhosis predictors of outcomes in a population with significant genotype 3 and 4 distribution.Liver Transpl. 2003; 9: 339-347Crossref PubMed Scopus (60) Google Scholar, 39Wali M.H. Heydtmann M. Harrison R.F. et al.Outcome of liver transplantation for patients infected by hepatitis C, including those infected by genotype 4.Liver Transpl. 2003; 9: 796-804Crossref PubMed Scopus (53) Google Scholar Potential reasons for the higher observed rate of advanced disease in patients with HCV genotype 4 may be a result of the long duration of infection in those who acquired the infection early in life via iatrogenic infection. Preliminary data from a French study reports a significantly higher rate of cirrhosis (29.8% vs 10.8%, P < .0001) and a longer duration of infection (27.0 ± 9.8 y vs 20.0 ± 6.5 y) in Egyptian immigrants residing in France compared with native French patients, the majority of whom are injection drug users.40Roulot BV, D. Fantain H. Bailly F. et al.Observational VHC4 Study GroupEpidemiology and response to treatment in patients infected by HCV genotype 4 in France compared to immigrant patients infected in Egypt.Hepatology. 2004; 40: 330AGoogle Scholar There were no significant age differences in the 2 groups (43.8 ± 10 y vs 44.7 ± 10 y), but exposure to HCV earlier in life likely accounts for the longer duration of infection in Egyptian patients. Therefore, studies of patients with HCV genotype 4 in Western countries need to account for ethnicity-related factors because this is a heterogenous population inclusive of 2 distinct subgroups: native injection drug users and immigrants from endemic regions with early iatrogenic acquisition of HCV infection. HCV genotype 5 is the predominant genotype in South Africa.41Smuts H.E. Kannemeyer J. Genotyping of hepatitis C virus in South Africa.J Clin Microbiol. 1995; 33: 1679-1681PubMed Google Scholar A study of 130 HCV-infected individuals (blood donors, chronic renal failure patients, adult outpatients, and hemophiliacs) from 3 regions of South Africa reported a prevalence of 39.2% for genotype 5, 33% for genotype 1, 21.5% for genotypes 2 and 3, and only 2.3% for genotype 4. Although relatively restricted to South Africa, HCV genotype 5 also can be seen in ethnically diverse European regions such as the Benelux countries.42van Doorn L.J. Kleter G.E. Stuyver L. et al.Sequence analysis of hepatitis C virus genotypes 1 to 5 reveals multiple novel subtypes in the Benelux countries.J Gen Virol. 1995; 76: 1871-1876Crossref PubMed Scopus (31) Google Scholar Most recently, HCV genotype 5 was reported at an unexpectedly high prevalence of 14.2% among largely settled, semirural inhabitants of central France who had not been at risk for acquiring HCV from other countries.43Henquell C. Cartau C. Abergel A. et al.High prevalence of hepatitis C virus type 5 in central France evidenced by a prospective study from 1996 to 2002.J Clin Microbiol. 2004; 42: 3030-3035Crossref PubMed Scopus (52) Google Scholar HCV genotype 5 probably is among the least known genotype of chronic hepatitis C. One of the very few studies of antiviral therapy for HCV genotype 5 to date was presented as an abstract by Bonny et al.44Bonny C. Roche C. Randl K. et al.Treatment of interferon-naïve patients with HCV genotype 5 with interferon (or PEG-interferon) plus ribavirin results in a very high sustained virological response.J Hepatol. 2003; 38: 738AAbstract Full Text PDF Google Scholar Their study was a retrospective study conducted in France comparing SVR rates in patients with HCV genotype 5 who underwent 48 weeks of treatment with IFN monotherapy or in combination with RBV. The overall SVR rate for combination therapy was significantly higher than that of IFN monotherapy (71% vs 31%, P < .05) and resembles that of genotypes 2 and 3 from pivotal trials (Figure 2).45McHutchison J.G. Gordon S.C. Schiff E.R. et al.Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3330) Google Scholar, 46Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5862) Google Scholar, 47Fried M.W. Shiffman M.L. Reddy K.R. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5832) Google Scholar Another French study directly compared SVR rates with either IFN + RBV or PEG IFN + RBV in patients with HCV genotype 5 (n = 12) with those with genotype 1 (n = 22) and 2 or 3 (n = 15) (Figure 2).48Legrand-Abravanel F. Sandres-Saune K. Barange K. et al.Hepatitis C virus genotype 5 epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin.J Infect Dis. 2004; 189: 1397-1400Crossref PubMed Scopus (52) Google Scholar SVR rates were similar between patients with genotypes 5 and 2 or 3 (63.6% and 66.6%, respectively), but significantly different between patients with genotype 5 and genotype 1 (63.6% vs 22.7%, P < .05). HCV genotype 6 and 6 subtypes (previously known as genotypes 7–9) have been found primarily in south China, Hong Kong, Taiwan, Macao, and southeast Asia including Singapore, Malaysia, Vietnam, Thailand, and Burma.2Simmonds P. Viral heterogeneity of the hepatitis C virus.J Hepatol. 1999; 31: 54-60Abstract Full Text PDF PubMed Google Scholar, 49Simmonds P. Mellor J. Sakuldamrongpanich T. et al.Evolutionary analysis of variants of hepatitis C virus found in South-East Asia comparison with classifications based upon sequence similarity.J Gen Virol. 1996; 77: 3013-3024Crossref PubMed Scopus (137) Google Scholar, 50Sugiyama K. Kato N. Nakazawa T. et al.Novel genotypes of hepatitis C virus in Thailand.J Gen Virol. 1995; 76: 2323-2327Crossref PubMed Scopus (23) Google Scholar, 51Tokita H. Okamoto H. Tsuda F. et al.Hepatitis C virus variants from Vietnam are classifiable into the seventh, eighth, and ninth major genetic groups.Proc Natl Acad Sci U S A. 1994; 91: 11022-11026Crossref PubMed Scopus (181) Google Scholar, 52Mellor J. Walsh E.A. Prescott L.E. et al.Survey of type 6 group variants of hepatitis C virus in Southeast Asia by using a core-based genotyping assay.J Clin Microbiol. 1996; 34: 417-423PubMed Google Scholar, 53Lao W. Prevalence of genotype 6 chronic hepatitis C infection in Hong Kong.J Gastroenterol Hepatol. 2002; 17: A142Google Scholar, 54Lu L. Nakano T. He Y. et al.Predominance of closely related HCV subtype 1B isolates throughout China and existence of new genotype 6 variants in Southern China.Hepatology. 2004; 40: 413ACrossref Scopus (146) Google Scholar HCV genotype 10a and 11a also have been found in southeast Asia, but only from Indonesia to date.55Tokita H. Okamoto H. Iizuka H. et al.Hepatitis C virus variants from Jakarta, Indonesia classifiable into novel genotypes in the second (2e and 2f), tenth (10a) and eleventh (11a) genetic groups.J Gen Virol. 1996; 77: 293-301Crossref PubMed Scopus (142) Google Scholar HCV genotype 10a is considered a divergent subtype of genotype 3 (3k), but genotype 11a is related closely to genotype 6 and is considered a subtype of genotype 6 (6g).3Farci P. Purcell R.H. Clinical significance of hepatitis C virus genotypes and quasispecies.Semin Liver Dis. 2000; 20: 103-126PubMed Google Scholar, 4Los Alamos National Laboratories. HCV nomenclature. Available at: www.hcv.lanl.gov/content/hcv-db/classification.genotable. Last updated: September 7, 2004 Accessed: January 14, 2005.Google Scholar, 56Adams N.J. Chamberlain R.W. Taylor L.A. et al.Complete coding sequence of hepatitis C virus genotype 6a.Biochem Biophys Res Commun. 1997; 234: 393-396Crossref PubMed Scopus (50) Google Scholar From studies of both blood donors and outpatients, the prevalence of HCV genotype 6 in Hong Kong is approximately 30% in Chinese patients in Hong Kong and Vietnamese patients in Vietnam and in the United States.51Tokita H. Okamoto H. Tsuda F. et al.Hepatitis C virus variants from Vietnam are classifiable into the seventh, eighth, and ninth major genetic groups.Proc Natl Acad Sci U S A. 1994; 91: 11022-11026Crossref PubMed Scopus (181) Google Scholar, 52Mellor J. Walsh E.A. Prescott L.E. et al.Survey of type 6 group variants of hepatitis C virus in Southeast Asia by using a core-based genotyping assay.J Clin Microbiol. 1996; 34: 417-423PubMed Google Scholar, 53Lao W. Prevalence of genotype 6 chronic hepatitis C infection in Hong Kong.J Gastroenterol Hepatol. 2002; 17: A142Google Scholar, 57Nguyen M.H. Garcia R.T. Ning J. et al.High prevalence of novel genotypes in Vietnamese patients with chronic hepatitis C.Gastroenterology. 2004; 126: 2020AAbstract Full Text Full Text PDF Scopus (4) Google Scholar In mainland China, HCV genotype 6 appears to be rare except in south China, where it is the second most common genotype after genotype 1b.54Lu L. Nakano T. He Y. et al.Predominance of closely related HCV subtype 1B isolates throughout China and existence of new genotype 6 variants in Southern China.Hepatology. 2004; 40: 413ACrossref Scopus (146) Google Scholar Although located in the vicinity of southeast Asia, the Philippines appears to have an HCV genotype distribution similar to that seen in the West.58Katayama Y. Barzaga N.G. Alipio A. et al.Genotype analysis of hepatitis C virus among blood donors and inmates in Metro Manila, The Philippines.Microbiol Immunol. 1996; 40: 525-529PubMed Google Scholar Southeast Asian immigrants in Australia treated with RBV 1000–1200 mg/day in divided doses and an induction dose of IFN 5 MU/day for 8 weeks and then 3 MU 3 times weekly for 44 weeks had an SVR of 62% with IFN + RBV for HCV genotype 1 and 82.5% for genotypes 6–9.5Dev A.T. McCaw R. Sundararajan V. et al.Southeast Asian patients with chronic hepatitis C the impact of novel genotypes and race on treatment outcome.Hepatology. 2002; 36: 1259-1265Crossref PubMed Scopus (84) Google Scholar In another study from Hong Kong, the SVR with IFN + RBV combination therapy for 52 weeks was 29% for genotype 1 and 62.5% for genotypes 6–9 (Figure 3).59Hui C.K. Yuen M.F. Sablon E. et al.Interferon and ribavirin therapy for chronic hepatitis C virus genotype 6 a comparison with genotype 1.J Infect Dis. 2003; 187: 1071-1074Crossref PubMed Scopus (61) Google Scholar The SVR in Vietnamese immigrants in California with HCV genotypes 6–9 treated with IFN + RBV combination therapy for 24 weeks was 61.1%.60Nguyen M.H. Trinh H.N. Keeffe E.B. et al.Evaluation and outcomes of combination therapy with interferon or peg-interferon plus ribavirin in 67 Southeast Asian patients with hepatitis C genotypes 6, 7, 8, and 9.Hepatology. 2003; 38: 644ACrossref Google Scholar The SVR rate to PEG IFN + RBV in this study was lower than the SVR with conventional IFN + RBV and likely was caused by a lower treatment completion rate in patients treated with PEG IFN + RBV (71% vs 91%); in addition, this observed difference was not statistically significant. These preliminary results suggest that the SVR rate to combination therapy with IFN + RBV may be somewhere between that seen in patients with genotype 1 and genotypes 2 and 3. The similar SVR rate from the latter 2 studies also raises the question whether 24 vs 48 or 52 weeks of antiviral therapy would lead to different SVR rates in patients with genotypes 6–9. A multicenter randomized controlled trial comparing SVR with 24 vs 48 weeks of PEG IFN + RBV in southeast Asian patients residing in the United States is currently underway." @default.
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