Predictors of the efficacy of interferon therapy in chronic hepatitis C virus infection. Tokyo-Chiba Hepatitis Research Group

Shiratori, Yasushi; Kato, Naoya; Yokosuka, Osamu; Imazeki, Fumio; Hashimoto, Etsuko; Hayashi, Naoaki; Nakamura, Akira; Asada, Mayumi; Kuroda, Hiromasa; Tanaka, Nobuyuki; Arakawa, Yasuyuki; Omata, Masao

doi:10.1053/gast.1997.v113.pm9247476

Cited by 184 publications

(145 citation statements)

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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%

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

et al. 1999

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“…Present data strongly indicate that HCV genotype is the key determinant of response to IFN-alpha-based treatment regimens [59][60][61][62].…”

Section: Molecular Epidemiology Of Hcv Genetic Diversity and Its Clinmentioning

confidence: 99%

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

Trinks

Gadano

Argibay

2012

Epidemiology Research International

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Hepatitis C virus (HCV) represents a major worldwide public health problem. The search for the key molecular biomarkers that may provide insight on the basis of the differences in disease progression, severity, and response to therapy is crucial for understanding the natural history of HCV, for estimating the burden of infection and for developing preventive interventions. Initially, molecular epidemiology studies have focused on studying the viral genetic diversity (genotypes, genetic variants, specific nucleotide and amino acid substitutions). However, the clinical heterogeneities of HCV infection and the imperfect predictability of the response to treatment have suggested the need to search for host genetic biomarkers. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as in treatment response and adverse effects, such asIL-28B,ITPA, andIP-10. As a consequence, nowadays the focus of molecular epidemiology studies has turned from the viral to the human genome. This paper will cover recent reports on the subject describing the most relevant viral as well as host genetic risk factors analyzed by past and current HCV molecular epidemiology studies.

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“…Sustained virologic response rate in 1b genotype high-virus-load infection is less than 10% with the licensed 6-month interferon monotherapy, in marked contrast to the rate of 60% in non-1b genotype infection. 11 Combination with ribavirin is known to improve the efficacy of interferon. 12 In Japan, the duration of the combination therapy is currently limited to 6 months, resulting in a response rate of only about 15% in 1b genotype high-virus-load infection.…”

Section: Treatment Of Chronic Hepatitis Cmentioning

confidence: 99%

Prevention and treatment of hepatocellular carcinoma

Omata

Yoshida

2004

Liver Transpl

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Viral hepatitis, by either hepatitis C virus (HCV) or hepatitis B virus (HBV), is the dominant cause of hepatocellular carcinoma (HCC). This is to say that HCC may be prevented by controlling viral infection. Horizontal transmission of HCV has become obsolete owing to the discovery of the virus. Vertical transmission of HBV during delivery has been effectively prevented by vaccination and immunization of neonates. The efficacy of interferon therapy against HCV was recently much improved. We now possess several powerful antiviral drugs against HBV. There has been progress also in the treatment of HCC, and together with advances in diagnostics facilitating HCC detection at an early stage, tumor nodules can often be completely removed either by medical ablation or surgical resection. Nevertheless, recurrence of HCC after apparently curative treatment is extraordinarily frequent, since the remaining liver is still at a particularly high risk of HCC. An effective treatment of HCC should include measures to control de novo carcinogenesis. (Liver Transpl 2004;10:S111-S114.)H epatocellular carcinoma (HCC) is unique among cancers in that the acquired factors are directly responsible for carcinogenesis in the majority of cases. In particular, HCV infection forms the predominant basis of HCC development in various countries, whereas HBV is the main etiology in regions where its infection is prevalent. In Japan, HCV is causative in 80% and HBV in 10% cases of HCC. 1 This implies two important things. First, it is possible to distinguish the patients at high risk for HCC, facilitating efficient screening for HCC development. Second, HCC can be prevented, at least theoretically, by controlling the acquired factor, viral infection. Prevention of Viral InfectionStrategies for HCC prevention can be made at two levels: the prevention of virus infection and the treatment of viral hepatitis. In Japan and other countries, neonates from HBV-positive mothers are treated with the combination of hepatitis B vaccination and hepatitis B immune globulin (HBIG). 2 This procedure has been practiced in Japan since the 1980s. It effectively prevents the infection during delivery, the main route of HBV transmission, although intrauterine infection remains a possibility. Thus, the rate of mother-neonate vertical transmission of HBV has been reduced down to one-twentieth of the previous rate. The prevalence of an HBV carrier in Japan is significantly lower among the younger generation than among the older ones. HBV prevention is said to be one of the most conspicuous achievements of public health policy.In Japan, HCV transmission also seems to have been decreasing for a couple of decades, possibly owing to the improved hygienics in general medical practice. However, we were not able to effectively prevent the blood transfusion-mediated HCV infection, or non-A, non-B hepatitis, as it was called then, until the discovery of HCV in the late 1980s. 3 With subsequent improvements in HCV detection, the occurrence of HCV infection has become virtually o...

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Predictors of the efficacy of interferon therapy in chronic hepatitis C virus infection. Tokyo-Chiba Hepatitis Research Group

Cited by 184 publications

References 1 publication

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

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

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

Prevention and treatment of hepatocellular carcinoma

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