Efficacy of low‐dose intermittent interferon‐alpha monotherapy in patients infected with hepatitis C virus genotype 1b who were predicted or failed to respond to pegylated interferon plus ribavirin combination therapy

Akuta, Norio; Suzuki, Fumitaka; Kawamura, Yusuke; Yatsuji, Hiromi; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Arase, Yasuji; Ikeda, Kenji; Kumada, Hiromitsu

doi:10.1002/jmv.21224

Cited by 12 publications

(9 citation statements)

References 30 publications

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“…In contrast, in the untreated group, the fibrosis score did not decline 144 . In Japan, several studies support the effectiveness of low‐dose IFN maintenance therapy 145–147 . In the USA, an RCT of 53 patients in whom a histological response, but not a viral response was induced by 6 MIU of IFN showed that 3 MIU of IFN for 24 months improved the degree of hepatic fibrosis.…”

Section: Monotherapy With Ifn or Peg‐ifnmentioning

confidence: 98%

Management of hepatitis C; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009)

Izumi

Nishiguchi

Hino

et al. 2010

Hepatology Research

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The consensus meeting for the diagnosis, management and treatment for hepatitis C was held in 45(th) annual meeting for the Japan Society of Hepatology (JSH) in June 2009 where the recommendations and informative statements were discussed including organizers and presenters. The Several important informative statements and recommendations have been shown. This was the fourth JSH consensus meeting of hepatitis C, however, the recommendations have not been published in English previously. Thus, this is the first report of JSH consensus of hepatitis C. The rate of development of hepatocellular carcinoma (HCC) in HCV-infected patients in Japan is higher than in the USA, because the average age of the HCV-infected patients is greater and there are more patients with severe fibrosis of the liver than in the USA. In Japan, more than 60% of HCV-infected patients are genotype 1b infection, and they show lower response to perinterferon and ribavirin combination treatment. To improve the response rate is also an important issue in our country. To establish the original recommendations and informative statements to prevent the development of HCC is a very important issue in Japan.

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Section: Monotherapy With Ifn or Peg‐ifnmentioning

confidence: 98%

Management of hepatitis C; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009)

Izumi

Nishiguchi

Hino

et al. 2010

Hepatology Research

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“…During the first 2 weeks, IFN in the conventional dose is given daily or three times a week. Patients who do not clear HCV RNA during the maximal treatment period of 8 weeks receive half the conventional dose of IFN indefinitely 8 …”

Section: Supplements To Guidelines For the Treatment Of Chronic Hepatmentioning

confidence: 99%

Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan

Kumada

Okanoue

Onji

et al. 2010

Hepatology Research

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In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13-36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2-8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 x 103/mm(3) prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted.

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“…Several viral genetic factors influence treatment outcomes, including mutations in NS5A-interferon sensitivity determining region (ISDR) (13,38) and the core region (4, 6). Akuta et al reported that HCV-core amino acid substitutions at positions 70 and 91 are significantly correlated with poor responses to peg-IFN-plus-RBV therapy (6) and with increased hepatocarcinogenesis (2,3). Furthermore, it was reported recently that the core amino acid 70 and amino acid 91 substitutions are associated with a poor response to peg-IFN, RBV, and telaprevir combination therapy, respectively (1).…”

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Analysis of Interferon Signaling by Infectious Hepatitis C Virus Clones with Substitutions of Core Amino Acids 70 and 91

Funaoka

Sakamoto

Suda

et al. 2011

J Virol

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Substitution of amino acids 70 and 91 in the hepatitis C virus (HCV) core region is a significant predictor of poor responses to peginterferon-plus-ribavirin therapy, while their molecular mechanisms remain unclear. Here we investigated these differences in the response to alpha interferon (IFN) by using HCV cell culture with R70Q, R70H, and L91M substitutions. IFN treatment of cells transfected or infected with the wild type or the mutant HCV clones showed that the R70Q, R70H, and L91M core mutants were significantly more resistant than the wild type. Among HCV-transfected cells, intracellular HCV RNA levels were significantly higher for the core mutants than for the wild type, while HCV RNA in culture supernatant was significantly lower for these mutants than for the wild type. IFN-induced phosphorylation of STAT1 and STAT2 and expression of the interferon-inducible genes were significantly lower for the core mutants than for the wild type, suggesting cellular unresponsiveness to IFN. The expression level of an interferon signal attenuator, SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type. Interleukin 6 (IL-6), which upregulates SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type, suggesting interferon resistance, possibly through IL-6-induced, SOCS3-mediated suppression of interferon signaling. Expression levels of endoplasmic reticulum (ER) stress proteins were significantly higher in cells transfected with a core mutant than in those transfected with the wild type. In conclusion, HCV R70 and L91 core mutants were resistant to interferon in vitro, and the resistance may be induced by IL-6-induced upregulation of SOCS3. Those mechanisms may explain clinical interferon resistance of HCV core mutants.Hepatitis C virus (HCV) is one of the most important pathogens causing liver-related morbidity and mortality. Approximately 3% of the worldwide population is infected with HCV, which represents 170 million people, and 3 million to 4 million individuals are newly infected each year (33,47,62). There is no therapeutic or prophylactic vaccine available for HCV. Antiviral treatment has been shown to improve liver histology and decrease the incidence of hepatocellular carcinoma in chronic hepatitis C (CHC) (17, 64). Current therapies for CHC consist of treatment with pegylated interferon (peg-IFN), which acts both as an antiviral and as an immunoregulatory cytokine, and ribavirin (RBV), an antiviral prodrug that interferes with RNA metabolism (16, 31). However, less than 50% of patients infected with HCV genotype 1 treated in this way achieve a sustained virological response (SVR) or a cure of the infection (14, 16). Given this situations, gaining a detailed understanding of the molecular mechanisms of interferon (IFN) resistance has been a high priority in academia and industry.The response to peg-IFN-plus-RBV treatment is affected by several viral and host factors, including age, gender (22, 23), grade of liver fibrosis (21, 42), HCV ge...

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Efficacy of low‐dose intermittent interferon‐alpha monotherapy in patients infected with hepatitis C virus genotype 1b who were predicted or failed to respond to pegylated interferon plus ribavirin combination therapy

Cited by 12 publications

References 30 publications

Management of hepatitis C; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009)

Management of hepatitis C; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009)

Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan

Analysis of Interferon Signaling by Infectious Hepatitis C Virus Clones with Substitutions of Core Amino Acids 70 and 91

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