HCV genotypes in chronic hepatitis C and response to interferon

Kanai, Koichi; Kako, Makoto; Okamoto, Hiroaki

doi:10.1016/0140-6736(92)91311-u

Cited by 283 publications

(127 citation statements)

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“…Several studies have described a correlation between virus type and the response to interferon treatment (Kanai et al, 1992;Takada et al, 1992;Yoshioka et al, 1992;Chemello et al, 1994;Hino et al, 1994;Tisminetzky et al, 1994) and it is possible that disease outcome also depends on virus type (Simmonds et al, 1996). Furthermore, the wide genetic diversity of HCV represents a major challenge for future vaccine development.…”

Section: Discussionmentioning

confidence: 99%

Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon

Ndjomou

Pybus

Matz

2003

Journal of General Virology

101

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Hepatitis C virus (HCV) is a blood-borne pathogen that poses a significant threat to public health worldwide. The genetic diversity and distribution of HCV genotypes in non-Western countries, particularly subSaharan Africa, is poorly documented. This study reports a phylogenetic analysis of core and NS5B gene sequences of 37 HCV strains sampled in Cameroon. A high level of genetic diversity of both genotypes 1 and 4 was found, indicating a unique pattern of long-term HCV infection that has not been observed elsewhere. These results lead to the hypothesis that these HCV genotypes originated and diversified in west Central Africa before spreading to other regions. INTRODUCTIONHepatitis C virus (HCV) is a leading global cause of liver disease. It is estimated that more than 170 million people worldwide are chronically infected with HCV and are at risk of developing liver cirrhosis and liver cancer (WHO, 1997).HCV is a single-stranded, positive-sense RNA virus, with a genome of 9?7 kb long containing a single ORF. The ORF encodes three structural proteins (including the capsid protein, core) and six non-structural proteins (including the RNA polymerase, NS5B). The ORF is flanked by two NCRs located at the 59 and 39 ends (Choo et al., 1991).HCV is genetically diverse and is classified into six major genotypes, each of which is divided further into several subtypes (Robertson et al., 1998). HCV genotypes differ at more than 30 % of nucleotides across the entire genome, while HCV subtypes vary at more than 20 % of sites (Simmonds, 1995). HCV genotypes show different geographical distributions and levels of diversity, reflecting their different epidemic histories and routes of transmission. HCV isolates from Western countries typically have limited sequence diversity, resulting from the recent introduction of a few strains (such as subtypes 1a, 1b and 3a) from endemic areas. These strains have spread rapidly through infected blood products and intravenous drug use (Pybus et al., 2001). The distribution of HCV genotypes in non-Western countries is less well documented, although small-scale surveys have found considerable sequence diversity of genotypes 1, 2 and 4 in African countries (Xu et al., 1994; Fretz et al., 1995;Ruggieri et al., 1996;Wansbrough-Jones et al., 1998;Jeannel et al., 1998), suggesting that these strains have been endemic to the continent for several hundred years (Smith et al., 1997; Pybus et al., 2001). The investigation of HCV genetic diversity in subSaharan Africa is, therefore, necessary to provide insights into the global epidemiology, epidemic history and origin of HCV. Furthermore, availability of more sequence data from subSaharan Africa may help to refine the HCV classification system.In this work we present a phylogenetic analysis of core and NS5B gene sequences obtained from 37 HCV strains isolated in Cameroon. We show that HCV genotypes 1 and 4 are both highly divergent in Cameroon, indicating the longterm presence of both strains in west Central Africa. This pattern of HCV endemicity i...

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Section: Discussionmentioning

confidence: 99%

Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon

Ndjomou

Pybus

Matz

2003

Journal of General Virology

101

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“…While the complete response is as low as 10% to 20% in HCV-1b infection, it is considered more than 60% in HCV-2 infection in Japan. [7][8][9][10][11][12] Such differences in interferon efficacy among various HCV genotypes suggest that a certain kind of genetic change of the virus could affect the sensitivity to interferon.We recently identified a region that is associated with the response to interferon in HCV-1b genomes in Japan. 13 An increase in the number of amino acid changes in the nonstructural protein 5A gene (NS5A) (NS5A2209-2248, interferon sensitivity determining region [ISDR]) makes HCV more sensitive to interferon.…”

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confidence: 99%

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confidence: 99%

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

et al. 1999

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An association has been reported between mutations in the amino acid residues 2209-2248 of the nonstructural protein 5A (NS5A) gene (interferon-sensitivity determining region [ISDR]) and interferon efficacy in hepatitis C virus (HCV)-1b infection. This relationship was analyzed in chronic HCV-2 infection. Forty patients with HCV-2a and 35 with HCV-2b were treated with interferon alfa for 6 months with a total dose of 468 to 860 million units. Pretreatment NS5A sequences were determined by direct sequencing. A higher complete and sustained response rate was observed in HCV-2a than in HCV-2b (70% vs. 34%; P ‫؍‬ .003). Serum HCV-RNA levels were lower in complete responders than nonresponders in HCV-2a (P ‫؍‬ .049) and HCV-2b (P ‫؍‬ .02). The number of amino acid mutations was greater in complete responders than nonresponders in NS5A2193- The current primary therapy for chronic hepatitis C is parenteral administration of type 1 interferons (interferon alfa and beta), while the rate of sustained and complete responses with virus eradication is obtained in only up to 30% of the patients. 1-3 To date, hepatitis C virus (HCV) is classified into at least 9 major genotypes and more than 30 subtypes. 4,5 In Japan, about 70% of the patients with chronic hepatitis C are infected with HCV genotype 1b (HCV-1b), and the rest are infected with HCV genotype 2 (HCV-2) 6 (25% with HCV-2a and 5% with HCV-2b). While the complete response is as low as 10% to 20% in HCV-1b infection, it is considered more than 60% in HCV-2 infection in Japan. [7][8][9][10][11][12] Such differences in interferon efficacy among various HCV genotypes suggest that a certain kind of genetic change of the virus could affect the sensitivity to interferon.We recently identified a region that is associated with the response to interferon in HCV-1b genomes in Japan. 13 An increase in the number of amino acid changes in the nonstructural protein 5A gene (NS5A) (NS5A2209-2248, interferon sensitivity determining region [ISDR]) makes HCV more sensitive to interferon. 14 However, the mechanism of the different response to interferon therapy among patients with HCV-2 infection is still unclear. Some studies suggested that a lower viral load is associated with the good response to interferon in HCV-1b or non-1b, 12,15 the mechanism of which is still unknown. In previous studies, interferon effect and pretreatment viral load were also associated with the mutations in ISDR in HCV-1b. 13,16 Thus, the relation between NS5A structure and interferon effect or viral load in HCV genotypes other than HCV-1b is of great interest.Several studies that focused on biological functions of NS5A revealed some aspects of its properties. In particular, Gale et al. 17 suggested that the NS5A protein inhibits an RNA-dependent protein kinase (PKR), which plays a major role in the viral protection by inhibiting viral protein translation. The NS5A protein of HCV-1b and -1a forms a complex with the PKR and inhibits the phosphorylation of eukaryotic translation initiation factor-2 (eIF-2). Mor...

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“…Several large treatment studies have indicated that high viral load, HCV genotype 1b, long disease duration and transfusion-acquired infection render response to IFN therapy less likely (8)(9)(10)(11)(12)(13). The response rate to IFN is inversely correlated to the HCV RNA concentration (14)(15)(16)(17).…”

Section: Hepatitis C Virus Genotypementioning

confidence: 99%

Patients with Chronic Hepatitis C - Who Should Not Be Treated?

Schüler

Manns

2000

Canadian Journal of Gastroenterology

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The decision to treat a patient with chronic hepatitis C (CHC) is based on what is known about the risk factors for developing liver cirrhosis or hepatocellular carcinoma, as well as on conditions that contraindicate therapy or impair therapy effectiveness. Several factors, including age, treatment side effects, disease severity, concurrent diseases and life conditions, may render treatment decisions more difficult. This review focuses on identifying CHC patients who should not receive treatment.

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HCV genotypes in chronic hepatitis C and response to interferon

Cited by 283 publications

References 3 publications

Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon

Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

Patients with Chronic Hepatitis C - Who Should Not Be Treated?

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