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Tahata Y, Sakamori R, Takehara T. Treatment progress and expansion in Japan: From interferon to direct-acting antiviral. Glob Health Med 2021; 3:321-334. [PMID: 34782876 DOI: 10.35772/ghm.2021.01083] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.
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Affiliation(s)
- Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Mawatari S, Oda K, Tabu K, Ijuin S, Kumagai K, Fujisaki K, Hashiguchi M, Inada Y, Uto H, Hiramine Y, Kure T, Hori T, Taniyama O, Kasai A, Tamai T, Moriuchi A, Ido A. The co-existence of NS5A and NS5B resistance-associated substitutions is associated with virologic failure in Hepatitis C Virus genotype 1 patients treated with sofosbuvir and ledipasvir. PLoS One 2018; 13:e0198642. [PMID: 29856885 PMCID: PMC5983500 DOI: 10.1371/journal.pone.0198642] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 05/22/2018] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs). METHODS Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed. RESULTS Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%). CONCLUSIONS Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.
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Affiliation(s)
- Seiichi Mawatari
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Department of HGF Tissue Repair and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Kazuaki Tabu
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Sho Ijuin
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Uearata-cho Kagoshima, Japan
| | - Kunio Fujisaki
- Department of Hepatology, Kirishima Medical Center, Kirishima, Hayato-cho, Kirishima, Kagoshima, Japan
| | - Masafumi Hashiguchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Department of Hepatology, Kirishima Medical Center, Kirishima, Hayato-cho, Kirishima, Kagoshima, Japan
| | - Yukiko Inada
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, Takamatsu-cho, Miyazaki, Japan
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, Takamatsu-cho, Miyazaki, Japan
| | - Yasunari Hiramine
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, Tenpozan-cho, Kagoshima, Japan
| | - Takeshi Kure
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, Tenpozan-cho, Kagoshima, Japan
| | - Takeshi Hori
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Uearata-cho Kagoshima, Japan
| | - Oki Taniyama
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Uearata-cho Kagoshima, Japan
| | - Ai Kasai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Tsutomu Tamai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Akihiro Moriuchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences,Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
- Department of HGF Tissue Repair and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
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3
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Fujii H, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Nakamura H, Yasui K, Minami M, Tanaka S, Ishikawa H, Kimura H, Takami S, Nagao Y, Shima T, Itoh Y. Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions. World J Hepatol 2017; 9:1064-1072. [PMID: 28951778 PMCID: PMC5596313 DOI: 10.4254/wjh.v9.i25.1064] [Citation(s) in RCA: 9] [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: 03/16/2017] [Revised: 05/17/2017] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate daclatasvir (DCV) and asunaprevir (ASV) efficacy in hepatitis C (HCV) patients, with respect to resistance-associated substitutions (RASs).
METHODS A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses (SVR) according to pretreatment factors (gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion (SVR12).
RESULTS The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/mL was significantly lower than those with viral loads of < 6.0 log IU/mL (P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative (P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure.
CONCLUSION Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 6050981, Japan
| | | | | | | | | | - Hideki Nakamura
- Department of Gastroenterology and Hepatology, North Medical Center, Kyoto Prefectural University of Medicine, Kyoto 6292261, Japan
| | | | - Masahito Minami
- Department of Internal Medicine, Aiseikai Yamashina Hospital, Kyoto 6078086, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara 6308305, Japan
| | - Hiroki Ishikawa
- Department of Gastroenterology and Hepatology, Omihachiman Community Medical Center, Shiga 5230082, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 6050981, Japan
| | - Shiro Takami
- Department of Gastroenterology, Otsu Municipal Hospital, Otsu 5200804, Japan
| | - Yasuyuki Nagao
- Department of Gastroenterology, Matsushita Memorial Hospital, Moriguchi 5708540, Japan
| | - Toshihide Shima
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 5640013, Japan
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Mawatari S, Oda K, Tabu K, Ijuin S, Kumagai K, Inada Y, Uto H, Hiramine Y, Kure T, Fujisaki K, Hashiguchi M, Hori T, Oshige A, Imanaka D, Saishoji A, Taniyama O, Sakae H, Tamai T, Moriuchi A, Ido A. New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir. J Gastroenterol 2017; 52:855-867. [PMID: 28078469 DOI: 10.1007/s00535-016-1303-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/22/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.
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Affiliation(s)
- Seiichi Mawatari
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Kazuaki Tabu
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Sho Ijuin
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Yukiko Inada
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan
| | - Yasunari Hiramine
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan
| | - Takeshi Kure
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan
| | - Kunio Fujisaki
- Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan
| | - Masafumi Hashiguchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan
| | - Takeshi Hori
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan
| | - Akihiko Oshige
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan
| | - Dai Imanaka
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Gastroenteroloby, Ikeda Hospital, 1830 Shimoharaigawa-cho, Kanoya, Kagoshima, 893-0024, Japan
| | - Akiko Saishoji
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Hepatology, Kagoshima Teishin Hospital, 1-12-1 Shimoishiki, Kagoshima, 890-8798, Japan
| | - Oki Taniyama
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Haruka Sakae
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Tsutomu Tamai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Akihiro Moriuchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
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Yan Z, Wang Y. Viral and host factors associated with outcomes of hepatitis C virus infection (Review). Mol Med Rep 2017; 15:2909-2924. [PMID: 28339063 DOI: 10.3892/mmr.2017.6351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/13/2017] [Indexed: 11/05/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host‑viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon‑α plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct‑acting antiviral therapy. HCV genome heterogeneity and baseline viral load are additionally associated with the treatment response. Multiple host genetic variants localized in genes associated with the immune response have been identified as predictors of spontaneous disease course and therapy outcome in chronic HCV. However, most findings from candidate gene association studies have not been proven universal for all investigated populations and independent studies. Previous findings in independent large genome wide association studies confirmed that interferon‑λ3 gene polymorphisms are associated with spontaneous clearance and treatment responsiveness. A polymorphism of the inosine triphosphatase gene has been identified as a protective factor against ribavirin‑induced anemia and dose reductions. Another genetic variant in the patatin‑like phospholipase domain containing 3 genes is associated with hepatic steatosis and fibrosis in patients with HCV. The present review focused on the identified viral and host factors associated with outcomes of patients with HCV, and assessed the involvement of viral and host genetics in the natural history and treatment outcomes of HCV infection. This will provide novel ideas concerning personalized prevention and individualized clinical management.
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Affiliation(s)
- Zehui Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
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6
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Abstract
Chronic infection with hepatitis C virus (HCV) is a global public health burden. It has been only several decades since this virus was first identified. In the meantime, a lot of progress has been made in the fight against HCV. Although the development of pegylated interferon (PEG-IFN) and its combination with ribavirin (RBV) has significantly increased effectiveness of IFN-based treatment, candidate patients must be assessed for eligibility prior to the treatment due to side effects of the regimens and the rates of sustained virological response (SVR) were only around 50%. In 2011, the protease inhibitor (PI) Telaprevir was firstly approved as a direct-acting antiviral (DAA) for hepatitis C. The second generation of PIs was subsequently introduced and, by adding PI to Peg-IFN/RBV, the SVR rates were found to be raised to up to 80%. Further, with the recent approval of the NS5A inhibitors and the NS5B polymerase inhibitors and with the SVR rates reaching 90% or greater using IFN-free, DAA combination regimens, it is now expected that the majority of patients with chronic hepatitis C can be cured of infection in the near future.
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7
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Inoue J, Kanno A, Wakui Y, Miura M, Kobayashi T, Morosawa T, Kogure T, Kakazu E, Ninomiya M, Fujisaka Y, Umetsu T, Takai S, Nakamura T, Shimosegawa T. Identification of Genotype 2 HCV in Serotype-1 Hepatitis C Patients Unresponsive to Daclatasvir plus Asunaprevir Treatment. TOHOKU J EXP MED 2017; 241:21-28. [PMID: 28049871 DOI: 10.1620/tjem.241.21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
It is important to determine the genotypes or serotypes of hepatitis C virus (HCV) in patients before treatment with direct-acting antiviral agents (DAAs), because the effects of DAAs differ among genotypes. In Japan, two tests for HCV typing are available clinically, but only serotyping, not genotyping, is approved by the public health insurance. Although most serotype-1 Japanese patients are infected with genotype 1b HCV, it is known that a small proportion of patients show different results from two typing methods. This study focused on such patients and the effectiveness of treatment with daclatasvir plus asunaprevir (DCV/ASV) was evaluated. We analyzed 644 DCV/ASV-treated patients with serotype 1 or genotype 1b, and among them, 166 serotype-1 patients received a commercial-based direct sequencing (DS) test for resistant-associated variants of genotype 1b HCV. We found four patients (2.4%) with DS test failure, suggesting that the PCR primers targeting genotype 1b may not match. Importantly, none of the four patients achieved a sustained virological response. Our in-house DS test analyzing the 5'-untranslated region and coding regions for NS4 and NS5B of HCV showed that three of the four patients were infected with genotype 2 HCV, and one patient was infected with genotype 1a HCV. No recombinant virus of different genotypes was found. This study indicates that a subset of serotype-1 hepatitis C patients is infected with HCV of genotype 2 or 1a in Japan and that DCV/ASV is not effective for such patients. Thus, attention should be paid to DAA treatment without HCV genotyping.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine
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Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein. Proc Natl Acad Sci U S A 2017; 114:2018-2023. [PMID: 28159892 DOI: 10.1073/pnas.1614623114] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.
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9
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Abdel-aty M, Fouad M, Sallam MM, Elgohary EA, Ismael A, Nawara A, Hawary B, Tag-Adeen M, Khaled S. Incidence of HCV induced-Esophageal varices in Egypt: Valuable knowledge using data mining analysis. Medicine (Baltimore) 2017; 96:e5647. [PMID: 28121921 PMCID: PMC5287945 DOI: 10.1097/md.0000000000005647] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Esophageal varices is one of the most important comorbidity related liver cirrhosis, patients usually presented with hematemesis, melena, or both, ultimately 20% is the mortality during the first attack, hence we aimed to investigate the incidence of such esophageal varices related chronic Hepatitis C virus (HCV) in randomized Egyptian population.One thousand eighteen Egyptian patients, aged between 17 and 58 years, positive for Hepatitis C virus genotype 4 (HCV-4) by enzyme linked immunosorbent assay Ab and HCV RNA-polymerase chain reaction were screened for the presence of esophageal varices.Incidence of esophageal varices was 62.3%; 635 patients, those with large Esophageal varices (LEVs) was 47.4%; 301 patients. Model for end-stage liver disease (MELD) score has not been significantly improved post variceal band ligation (VBL). Using 2D U/S was useful for EVs prediction.Incidence of esophageal varices in HCV Egyptian patients still high, valuable knowledge would be helpful in clinical field have been discovered by data mining computational intelligent analysis using in practical medicine to improve overall health care.
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Affiliation(s)
- Mahmoud Abdel-aty
- Department of Mathematics and Information Technology, Zewail City for Biosciences and Technology, Giza
| | - Mahmoud Fouad
- Department of Gynecology and Obstetrics, Al Azhar Asuit Faculty of Medicine, Al Azhar University
| | - Mohammad M. Sallam
- Department of Internal Medicine, Zagazig Faculty of Medicine, Zagazig University
| | - Elsayed A. Elgohary
- Department of Internal Medicine, Zagazig Faculty of Medicine, Zagazig University
| | - Ali Ismael
- Department of Internal Medicine, Zagazig Faculty of Medicine, Zagazig University
| | - Abdallah Nawara
- Department of Internal Medicine, Zagazig Faculty of Medicine, Zagazig University
| | - Baha Hawary
- Department of Pediatrics and Neonatology, Aswan School of Medicine, Aswan University
| | - Mohammed Tag-Adeen
- Department of Internal Medicine, Qena Faculty of Meidicne, South Valley University
- Department of Gastroenetrology, Nagazaki School of medicine, Nagazaki University, Japan
| | - Salama Khaled
- Department of Gastroenterology and Hepatology, Nasser Institute Hospital for Research and Therapy, Cairo, Egypt
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10
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Kan T, Hashimoto S, Kawabe N, Murao M, Nakano T, Shimazaki H, Nakaoka K, Ohki M, Takagawa Y, Kurashita T, Takamura T, Yoshioka K. The clinical features of patients with a Y93H variant of hepatitis C virus detected by a PCR invader assay. J Gastroenterol 2016; 51:63-70. [PMID: 25904097 DOI: 10.1007/s00535-015-1080-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 04/07/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Resistance-associated variants (RAVs) reduce the efficacy of interferon (IFN)-free therapy with asunaprevir and daclatasvir for patients infected with hepatitis C virus (HCV) genotype 1b. The characteristics of patients with an L31 or a Y93 variant in the nonstructural 5A region detected by a polymerase chain reaction invader assay were investigated. METHODS In total, 201 patients with HCV genotype 1b were examined for L31F/M/V variants or a Y93H variant by the polymerase chain reaction invader assay. RESULTS L31M and Y93H variants were detected in 4.6 and 21.4 % of patients, respectively. Patients with an L31M variant had no significant characteristics. Patients with a Y93H variant had significantly higher HCV RNA levels (6.5 ± 0.5 log copies per milliliter vs 6.1 ± 0.7 log copies per milliliter, p = 0.0002), higher frequency of mutant type of the IFN-sensitivity-determining region (88.4 % vs 71.7 %, p = 0.0251), and higher frequency of TT genotype at rs8099917 of IL28B (91.7 % vs 54.3 %, p < 0.0001) than those with Y93 wild-type strains. Multivariate analysis identified HCV RNA levels [odds ratio (OR) 3.72, 95 % confidence interval (CI) 1.71-8.06, p = 0.0009] and TT genotype at rs8099917 (OR 7.45, 95 % CI 2.11-26.4, p = 0.0018) as factors associated with the presence of a Y93H variant. CONCLUSION The presence of a Y93H variant was associated with higher HCV RNA levels and TT genotype at rs8099917 of IL28B. Thus, patients with a Y93H variant may be ideal candidates for IFN-based therapy rather than IFN-free therapy, although the high viral load of these patients may reduce the response rate of IFN-based therapy.
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Affiliation(s)
- Toshiki Kan
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Senju Hashimoto
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Naoto Kawabe
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Michihito Murao
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Takuji Nakano
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Hiroaki Shimazaki
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Kazunori Nakaoka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Masashi Ohki
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Yuka Takagawa
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Takamitsu Kurashita
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Tomoki Takamura
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Kentaro Yoshioka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan.
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11
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Kumthip K, Maneekarn N. The role of HCV proteins on treatment outcomes. Virol J 2015; 12:217. [PMID: 26666318 PMCID: PMC4678629 DOI: 10.1186/s12985-015-0450-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 12/09/2015] [Indexed: 12/19/2022] Open
Abstract
For many years, the standard of treatment for hepatitis C virus (HCV) infection was a combination of pegylated interferon alpha (Peg-IFN-α) and ribavirin for 24–48 weeks. This treatment regimen results in a sustained virologic response (SVR) rate in about 50 % of cases. The failure of IFN-α-based therapy to eliminate HCV is a result of multiple factors including a suboptimal treatment regimen, severity of HCV-related diseases, host factors and viral factors. In recent years, advances in HCV cell culture have contributed to a better understanding of the viral life cycle, which has led to the development of a number of direct-acting antiviral agents (DAAs) that target specific key components of viral replication, such as HCV NS3/4A, HCV NS5A, and HCV NS5B proteins. To date, several new drugs have been approved for the treatment of HCV infection. Application of DAAs with IFN-based or IFN-free regimens has increased the SVR rate up to >90 % and has allowed treatment duration to be shortened to 12–24 weeks. The impact of HCV proteins in response to IFN-based and IFN-free therapies has been described in many reports. This review summarizes and updates knowledge on molecular mechanisms of HCV proteins involved in anti-IFN activity as well as examining amino acid variations and mutations in several regions of HCV proteins associated with the response to IFN-based therapy and pattern of resistance associated amino acid variants (RAV) to antiviral agents.
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Affiliation(s)
- Kattareeya Kumthip
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Niwat Maneekarn
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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12
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Abdel-Ghaffar TY, Sira MM, El Naghi S. Hepatitis C genotype 4: The past, present, and future. World J Hepatol 2015; 7:2792-2810. [PMID: 26668691 PMCID: PMC4670951 DOI: 10.4254/wjh.v7.i28.2792] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 09/24/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) genotype (GT) 4 represents 12%-15% (15-18 million) of total global HCV infection. It is prevalent in Northern and Equatorial Africa and the Middle East, and is also present in some countries in Europe. GT-4 (and subtype 4a in particular) dominates the HCV epidemic in Egypt. In underdeveloped countries, risk factors associated with HCV infection may be due to unsafe medical practices or other factors such as familial transmission, mother's HCV status, or illiteracy. HCV prevention and control programs should include health education, increased community awareness towards the disease, controlling infection distribution in health-care centers, proper sterilization of medical and dental instruments, and ensuring safe supply of blood and blood-products. Response rates to a 48-wk combined pegylated-interferon (PEG-IFN) and ribavirin (RBV) treatment range from 40%-69%, and HCV-GT-4 has been considered better than GT-1 but worse than GT-2 and GT-3 in treatment with PEG-IFN/RBV. However, with the introduction of the HCV-GT-1 effective protease inhibitors boceprevir and telaprevir in 2011, HCV-GT-4 became the "most difficult (GT) to treat". Recently, the direct-acting antivirals (DAAs) with pan- genotypic activities simeprevir, sofosbuvir, and daclatasvir have been recommended in triple regimens with PEG-IFN/RBV for the treatment of HCV-GT-4. An IFN-free regimen will be available for treatment of all genotypes of HCV in the near future. To date, several DAAs have been developed and are currently being evaluated in various combinations in clinical trials. As new regimens and new agents are being approved by the Food and Drug Administration, we can expect the guidelines for HCV treatment to be changed. The availability of shorter, simpler, and more tolerable treatment regimens can reduce the morbidity and mortality associated with HCV infection. With such a large number of therapeutic agents available, we can end up with a range of choices that we can select from to treat patients.
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Affiliation(s)
| | - Mostafa M Sira
- Tawhida Y Abdel-Ghaffar, Pediatric Department, Ain Shams University, Cairo 11566, Egypt
| | - Suzan El Naghi
- Tawhida Y Abdel-Ghaffar, Pediatric Department, Ain Shams University, Cairo 11566, Egypt
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13
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Fujii H, Nishimura T, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Sumida Y, Mitsuyoshi H, Yokomizo C, Tanaka S, Ishikawa H, Nishioji K, Kimura H, Takami S, Nagao Y, Takeuchi T, Shima T, Sawa Y, Minami M, Yasui K, Itoh Y. Comparison of peg-interferon, ribavirin plus telaprevir vs simeprevir by propensity score matching. World J Hepatol 2015; 7:2841-8. [PMID: 26668696 PMCID: PMC4670956 DOI: 10.4254/wjh.v7.i28.2841] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/22/2015] [Accepted: 11/10/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To compare efficacy of telaprevir (TVR) and simeprevir (SMV) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) while treating chronic hepatitis C (CHC). METHODS In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk (SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated. RESULTS Overall rates of SVR12 [undetectable serum hepatitis C virus (HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B (IL28B) genotype (rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds (n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28B genotype (rs8099917) as the only independent predictive factor of SVR12 in both groups. CONCLUSION SVR12 rates were almost identical following propensity score matching.
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Affiliation(s)
- Hideki Fujii
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takeshi Nishimura
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Umemura
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Taichiro Nishikawa
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kanji Yamaguchi
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Michihisa Moriguchi
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yoshio Sumida
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hironori Mitsuyoshi
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Chihiro Yokomizo
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Saiyu Tanaka
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hiroki Ishikawa
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kenichi Nishioji
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hiroyuki Kimura
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shiro Takami
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yasuyuki Nagao
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takayuki Takeuchi
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Toshihide Shima
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yoshihiko Sawa
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Masahito Minami
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kohichiroh Yasui
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Hideki Fujii, Takeshi Nishimura, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Masahito Minami, Kohichiroh Yasui, Yoshito Itoh, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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14
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Karchava M, Waldenström J, Parker M, Hallack R, Sharvadze L, Gatserelia L, Chkhartishvili N, Dvali N, Dzigua L, Dolmazashvili E, Norder H, Tsertsvadze T. High incidence of the hepatitis C virus recombinant 2k/1b in Georgia: Recommendations for testing and treatment. Hepatol Res 2015; 45:1292-8. [PMID: 25689487 PMCID: PMC4787595 DOI: 10.1111/hepr.12505] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 01/23/2015] [Accepted: 02/10/2015] [Indexed: 02/06/2023]
Abstract
AIM The first hepatitis C virus (HCV) recombinant, RF2k/1b, was initially described from Russia and has since then been identified from patients in Ireland, Estonia, Uzbekistan and Cyprus. Many of these patients originated from Georgia; however, there is no information on its prevalence in Georgia or its susceptibility to antiviral treatment. METHODS We retrospectively sequenced the non-structural region 5B (NS5B) of the HCV genome in samples from 72 Georgian patients, 36 of whom had been treated with pegylated interferon and ribavirin. RESULTS The HCV genotype was determined using the Versant HCV Genotype v2 kit. Based on this typing, 32 patients (44.4%) were infected with genotype 1, 21 (29.1%) genotype 2 and 19 (26.3%) genotype 3. Partial NS5B of these strains was sequenced and analyzed for type, with concordant genotype results for all type 1 and 3 strains. Discrepant results were observed for genotyped 2 strains, with 16 (76%) having NS5B of subtype 1b. On phylogenetic analysis, 15 NS5B sequences of these strains were found in a clade formed by recombinant RF2k/1b strains. The remaining discordant sequence was found within a clade formed by 1b strains. CONCLUSION Our findings show that the RF2k/1b recombinant strain is common among Georgian patients previously assumed to be infected with genotype 2. Because genotyping is mainly performed to decide treatment strategies, there is a need to determine the genotype by analysis of at least two genomic regions in strains from Georgian patients considered infected with genotype 2 based on standard HCV genotyping methods.
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Affiliation(s)
- Marine Karchava
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address
| | - Jesper Waldenström
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Monica Parker
- David Axelrod Institute, Wadsworth Center, Albany, NY, US
| | - Renee Hallack
- David Axelrod Institute, Wadsworth Center, Albany, NY, US
| | - Lali Sharvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address,Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Lana Gatserelia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address
| | - Nikoloz Chkhartishvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address
| | - Natia Dvali
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address
| | - Lela Dzigua
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address
| | | | - Helene Norder
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Tengiz Tsertsvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia address,Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
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15
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Enomoto H, Nishiguchi S. Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C. World J Hepatol 2015; 7:2681-2687. [PMID: 26609345 PMCID: PMC4651912 DOI: 10.4254/wjh.v7.i26.2681] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 10/15/2015] [Accepted: 11/03/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a major health concern worldwide. Interferon-α (IFN-α) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFN-based treatments for chronic HCV infection still have a clinical impact, particularly for patients with high risk conditions of developing hepatocellular carcinoma, such as older age and advanced liver fibrosis. As a result of exhaustive research, several viral factors, including NS5A amino acid mutations such as the IFN sensitivity-determining region and the IFN/ribavirin resistance-determining region, and mutations of amino acids in the core protein region (core 70 and 91) were shown to be associated with the response to IFN-α treatment. In addition, among the host factors related to the response to IFN-α treatment, polymorphisms of the interleukin-28B gene were identified to be the most important factor. In this article, we review the factors associated with the efficacy of IFN-α treatment for chronic HCV infection. In addition, our recent findings regarding the possible involvement of anti-IFN-α neutralizing antibodies in a non-response to pegylated-IFN-α treatment are also described.
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Affiliation(s)
- Hirayuki Enomoto
- Hirayuki Enomoto, Shuhei Nishiguchi, Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Shuhei Nishiguchi
- Hirayuki Enomoto, Shuhei Nishiguchi, Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
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16
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Deep sequencing and phylogenetic analysis of variants resistant to interferon-based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus. J Virol 2015; 89:6105-16. [PMID: 25810555 DOI: 10.1128/jvi.03127-14] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 03/20/2015] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Because of recent advances in deep sequencing technology, detailed analysis of hepatitis C virus (HCV) quasispecies and their dynamic changes in response to direct antiviral agents (DAAs) became possible, although the role of quasispecies is not fully understood. In this study, to clarify the evolution of viral quasispecies and the origin of drug-resistant mutations induced by interferon (IFN)-based protease inhibitor therapy, the nonstructural-3 (NS3) region of genotype 1b HCV in 34 chronic hepatitis patients treated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) was subjected to a deep sequencing study coupled with phylogenetic analysis. Twenty-six patients (76.5%) achieved a sustained viral response (SVR), while 8 patients did not (non-SVR; 23.5%). When the complexity of the quasispecies was expressed as the mutation frequency or Shannon entropy value, a significant decrease in the IFNL3 (rs8099917) TT group and a marginal decrease in the SVR group were found soon (12 h) after the introduction of treatment, whereas there was no decrease in the non-SVR group and no significant decrease in mutation frequency in the IFNL3 TG/GG group. In the analysis of viral quasispecies composition in non-SVR patients, major populations greatly changed, accompanied by the appearance of resistance, and the compositions were unlikely to return to the pretreatment composition even after the end of therapy. Clinically TVR-resistant variants were observed in 5 non-SVR patients (5/8, 62.5%), all of which were suspected to have acquired resistance by mutations through phylogenetic analysis. In conclusion, results of the study have important implications for treatment response and outcome in interferon-based protease inhibitor therapy. IMPORTANCE In the host, hepatitis C virus (HCV) consists of a variety of populations (quasispecies), and it is supposed that dynamic changes in quasispecies are closely related to pathogenesis, although this is poorly understood. In this study, recently developed deep sequencing technology was introduced, and changes in quasispecies associated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) triple therapy and their clinical significance were investigated extensively by phylogenetic tree analysis. Through this study, the associations among treatment response, changes in viral quasispecies complexity in the early stage of treatment, changes in the quasispecies composition, and origin of TVR-resistant variant HCV were elucidated.
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Miura M, Maekawa S, Sato M, Komatsu N, Tatsumi A, Takano S, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Enomoto N. Deep sequencing analysis of variants resistant to the non-structural 5A inhibitor daclatasvir in patients with genotype 1b hepatitis C virus infection. Hepatol Res 2014; 44:E360-7. [PMID: 24612030 DOI: 10.1111/hepr.12316] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/12/2014] [Accepted: 02/14/2014] [Indexed: 12/11/2022]
Abstract
AIM Daclatasvir, a non-structural (NS)5A replication complex inhibitor, is a potent and promising direct antiviral agent (DAA) for hepatitis C virus (HCV), being most effective in genotype 1b infection. Although it is known that genotype 1b viruses with Y93H and/or L31M/V/F mutations have strong resistance to daclatasvir, it is not known whether there are some clinical background conditions that favor the occurrence of HCV carrying those NS5A mutations. METHODS In this study, we carried out deep sequencing analysis of stored sera to determine the presence and significance of daclatasvir-resistant mutants in 110 genotype 1b HCV-infected patients with no previous daclatasvir treatment. RESULTS Deep sequencing analysis revealed that the NS5A L31M/V/F and Y93H mutations were present in 13 (11.8%) and 34 (30.9%) of the 110 patients, respectively, and significantly more frequently than in the control plasmid. Simultaneous L31M/V/F and Y93H mutations were detected in four of the 110 patients (3.6%). When the clinical relevance of NS5A resistance was investigated, Y93H was significantly correlated with the IL28B major (TT) genotype of the host (P = 0.042). CONCLUSION Y93H was detected frequently by deep sequencing in daclatasvir treatment-naïve patients. Importantly, it seems that the IL28B status of the patients may influence the presence of Y93H mutations, resulting in different treatment responses to daclatasvir.
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Affiliation(s)
- Mika Miura
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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Molecular basis of interferon resistance in hepatitis C virus. Curr Opin Virol 2014; 8:38-44. [DOI: 10.1016/j.coviro.2014.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 05/15/2014] [Accepted: 05/19/2014] [Indexed: 02/08/2023]
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El-Shamy A, Hotta H. Impact of hepatitis C virus heterogeneity on interferon sensitivity: an overview. World J Gastroenterol 2014; 20:7555-69. [PMID: 24976696 PMCID: PMC4069287 DOI: 10.3748/wjg.v20.i24.7555] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/18/2014] [Accepted: 04/21/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.
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20
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Ochi H, Miki D, Hayes CN, Abe H, Hayashida Y, Kubo M, Chayama K. IFNL4/IL-28B haplotype structure and its impact on susceptibility to hepatitis C virus and treatment response in the Japanese population. J Gen Virol 2014; 95:1297-1306. [PMID: 24646752 DOI: 10.1099/vir.0.060103-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A new type III interferon, IFN lambda 4 (IFNL4), and its single-nucleotide polymorphism (SNP) ss469415590 causing a frame shift have been recently reported strongly to affect antiviral therapy for chronic hepatitis C virus (HCV) infection in African and Caucasian populations compared to previously reported IL-28B SNPs rs12979860 and rs8099917. To compare the predictability for treatment outcome among those polymorphisms, we estimated haplotype structure of IFNL4/IL-28B consisting of the three SNPs in 4630 Japanese chronic hepatitis C patients and 1122 healthy controls and then compared their impact on response to pegylated-IFN (PEG-IFN) plus ribavirin (RBV) combined therapy in 903 HCV-1b-infected patients. A total of five haplotypes were identified, although two major haplotypes accounted for >99 % of the variation. The SNPs were tightly linked but not in absolute linkage disequilibrium. We could not find any difference in the predictive impact of any of these three SNPs with regard to susceptibility to HCV and treatment response. However, patients with favourable rs8099917 TT, linked to unfavourable genotypes of ss469415590 and rs12979860, showed poor initial viral response compared with those with all favourable genotypes (P = 0.0022). These findings suggest that, in part, ss469415590 and rs12979860 may have better predictive impact on response to PEG-IFN plus RBV therapy in the Japanese population, especially in patients with any of the minor haplotypes consisting of these SNPs.
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Affiliation(s)
- Hidenori Ochi
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasufumi Hayashida
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
| | - Kazuaki Chayama
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Konishi H, Motomura T, Matsumoto Y, Harimoto N, Ikegami T, Yoshizumi T, Soejima Y, Shirabe K, Fukuhara T, Maehara Y. Interferon-lambda4 genetic polymorphism is associated with the therapy response for hepatitis C virus recurrence after a living donor liver transplant. J Viral Hepat 2014; 21:397-404. [PMID: 24750545 DOI: 10.1111/jvh.12154] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The standard therapy against hepatitis C virus (HCV) recurrence postliver transplantation includes interferon (IFN)α and ribavirin. IFNL4 ss469415590 polymorphism has been reported as a novel predictor of the response to IFN therapy for chronic HCV infection. We examined the impact of IFNL4 polymorphism on the responsiveness to IFN therapy after liver transplantation. Tissue specimens were collected from 80 HCV-infected recipients and 78 liver donors, and their IFNL4 ss469415590 genotype, hepatic IFNL4 and interferon-stimulated genes' mRNA expression levels were examined. The association of the polymorphism and expression levels in terms of the IFN therapy response to HCV recurrence was analysed. Most individuals who had rs8099917 risk alleles also had ss469415590 risk alleles (R(2) = 0.9). Sustained virological response (SVR) rates were higher in both liver graft recipients and transplants with ss469415590 TT/TT alleles than in those with the risk ΔG allele (P = 0.003 and P = 0.005, respectively). In recipients with ss469415590 TT/TT, IFNL4 TT mRNA levels showed no significant differences between livers of patients who responded to therapy and those who did not (P = 0.4). In recipients with the risk ΔG allele, IFNL4 ΔG mRNA expression levels were significantly lower in SVR patients than in non-SVR patients (P = 0.02). Hepatic interferon stimulable genes and IFNL4 mRNA expression were correlated. Our findings suggest that analysing the ss469415590 genotype and IFNL4 ΔG expression provides a novel prediction strategy for the possible response to IFN therapy after liver transplantation.
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Affiliation(s)
- H Konishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba city, Japan
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Bai F, Yano Y, Kim SR, Seo Y, Miki A, Saito M, Hirano H, Momose K, Minami A, Hatazawa Y, Hayakumo T, Widasari DI, Rinonce HT, Sugano M, Tani S, Yoon S, Imoto S, Azuma T, Hotta H, Hayashi Y. Mutational diversity of NS5A and NS3 during triple therapy (telaprevir, pegylated-interferon-α 2b and ribavirin) for genotype 1b chronic hepatitis C: The Kobe Hepatitis Therapeutic Group. Int J Mol Med 2014; 33:1652-6. [PMID: 24647743 DOI: 10.3892/ijmm.2014.1706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Accepted: 02/26/2014] [Indexed: 11/05/2022] Open
Abstract
Telaprevir, a non-structural (NS)3/4A protease inhibitor, is a direct-acting antiviral drug that inhibits viral replication. Triple therapy with telaprevir, pegylated interferon, and ribavirin is a standard therapeutic regimen for patients with genotype 1b chronic hepatitis C virus (HCV) infection and a high viral load. Several factors, including mutations in the NS5A gene, are important predictors of the efficacy of interferon therapy. In this study, we examined the mutational diversity of NS5A and its impact on the efficacy of triple therapy. We enrolled patients with genotype 1b chronic HCV infection and a high viral load (31 males/17 females; mean age, 57.6 years), who were treated with triple therapy. This study was conducted at Kobe University Hospital and at three affiliated hospitals in Hyogo prefecture, Japan, between November 2011 and June 2013. A sustained viral response after 12 weeks (SVR12) was achieved in 37/48 patients (77%). Based on intent-to-treat analysis, SVR12 was significantly greater in patients with the major allele than in those with the minor allele for the IL28B single nucleotide polymorphism (SNP; 88 vs. 56%; P<0.05). The prevalence of the V2334I mutation in NS5A was significantly higher in patients who achieved SVR12, while that of G2356E was significantly higher in patients who did not achieve SVR12 (P<0.05). Mutations in the NS3 region that are thought to confer resistance to telaprevir were detected in 3/27 patients who achieved SVR12 (Val36, n=3) and in 5/10 patients who did not achieve SVR12 (Val36, n=4; Thr54, n=1). In conclusion, the IL28B SNP and mutations in the NS5A region were associated with the therapeutic response to triple therapy. Half of the patients who did not achieve SVR12 had mutations conferring resistance to telaprevir. However, pre-existing mutations in NS3 did not affect the efficacy of triple therapy.
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Affiliation(s)
- Fugui Bai
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Yoshihiko Yano
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Soo-Ryang Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Hyogo 653-0801, Japan
| | - Yasushi Seo
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Akira Miki
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Masaya Saito
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Hirotaka Hirano
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Kenji Momose
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Akihiro Minami
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Yuri Hatazawa
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Takanobu Hayakumo
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Dewiyani Indah Widasari
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Hanggoro Tri Rinonce
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | | | - Satoshi Tani
- Division of Internal Medicine, Konan Hospital, Kobe, Hyogo 658-0064, Japan
| | - Seitetsu Yoon
- Department of Gastroenterology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Hyogo 675-8555, Japan
| | | | - Takeshi Azuma
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Hak Hotta
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Yoshitake Hayashi
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
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Nakamoto S, Kanda T, Wu S, Shirasawa H, Yokosuka O. Hepatitis C virus NS5A inhibitors and drug resistance mutations. World J Gastroenterol 2014; 20:2902-2912. [PMID: 24659881 PMCID: PMC3961994 DOI: 10.3748/wjg.v20.i11.2902] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 10/23/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for "difficult-to-treat" HCV-infected patients. "First generation" HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. "Second generation" NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.
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24
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Kato N, Sejima H, Ueda Y, Mori K, Satoh S, Dansako H, Ikeda M. Genetic characterization of hepatitis C virus in long-term RNA replication using Li23 cell culture systems. PLoS One 2014; 9:e91156. [PMID: 24625789 PMCID: PMC3953375 DOI: 10.1371/journal.pone.0091156] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 02/10/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The most distinguishing genetic feature of hepatitis C virus (HCV) is its remarkable diversity and variation. To understand this feature, we previously performed genetic analysis of HCV in the long-term culture of human hepatoma HuH-7-derived HCV RNA-replicating cell lines. On the other hand, we newly established HCV RNA-replicating cell lines using human hepatoma Li23 cells, which were distinct from HuH-7 cells. METHODOLOGY/PRINCIPAL FINDINGS Li23-derived HCV RNA-replicating cells were cultured for 4 years. We performed genetic analysis of HCVs recovered from these cells at 0, 2, and 4 years in culture. Most analysis was performed in two separate parts: one part covered from the 5'-terminus to NS2, which is mostly nonessential for RNA replication, and the other part covered from NS3 to NS5B, which is essential for RNA replication. Genetic mutations in both regions accumulated in a time-dependent manner, and the mutation rates in the 5'-terminus-NS2 and NS3-NS5B regions were 4.0-9.0×10(-3) and 2.7-4.0×10(-3) base substitutions/site/year, respectively. These results suggest that the variation in the NS3-NS5B regions is affected by the pressure of RNA replication. Several in-frame deletions (3-105 nucleotides) were detected in the structural regions of HCV RNAs obtained from 2-year or 4-year cultured cells. Phylogenetic tree analyses clearly showed that the genetic diversity of HCV was expanded in a time-dependent manner. The GC content of HCV RNA was significantly increased in a time-dependent manner, as previously observed in HuH-7-derived cell systems. This phenomenon was partially due to the alterations in codon usages for codon optimization in human cells. Furthermore, we demonstrated that these long-term cultured cells were useful as a source for the selection of HCV clones showing resistance to anti-HCV agents. CONCLUSIONS/SIGNIFICANCE Long-term cultured HCV RNA-replicating cells are useful for the analysis of evolutionary dynamics and variations of HCV and for drug-resistance analysis.
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Affiliation(s)
- Nobuyuki Kato
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
- * E-mail:
| | - Hiroe Sejima
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
| | - Youki Ueda
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
| | - Kyoko Mori
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
| | - Shinya Satoh
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
| | - Hiromichi Dansako
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
| | - Masanori Ikeda
- Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan
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Belema M, Lopez OD, Bender JA, Romine JL, St Laurent DR, Langley DR, Lemm JA, O'Boyle DR, Sun JH, Wang C, Fridell RA, Meanwell NA. Discovery and development of hepatitis C virus NS5A replication complex inhibitors. J Med Chem 2014; 57:1643-72. [PMID: 24621191 DOI: 10.1021/jm401793m] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.
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Affiliation(s)
- Makonen Belema
- Department of Discovery Chemistry, ‡Department of Virology Discovery, and §Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
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Wu S, Kanda T, Nakamoto S, Imazeki F, Yokosuka O. Hepatitis C virus protease inhibitor-resistance mutations: our experience and review. World J Gastroenterol 2013; 19:8940-8948. [PMID: 24379619 PMCID: PMC3870547 DOI: 10.3748/wjg.v19.i47.8940] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 11/08/2013] [Accepted: 12/03/2013] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.
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Kuznetsova T, Tallo T, Brjalin V, Reshetnjak I, Salupere R, Priimagi L, Katargina O, Smirnova M, Jansons J, Tefanova V. Amino Acid Polymorphisms Within the Entire HCV NS5A Region in Estonian Chronic HCV 1b Patients With Different Treatment Response. HEPATITIS MONTHLY 2013; 13:e14481. [PMID: 24358043 PMCID: PMC3867023 DOI: 10.5812/hepatmon.14481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 09/29/2013] [Accepted: 11/01/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND A substantial proportion of hepatitis C virus (HCV)-1b infected patients do not response to pegylated interferon-α plus ribavirin (PegIFNα/RBV) combination therapy that was partially associated with mutations in the non-structural 5A (NS5A) protein. OBJECTIVES Analysis of NS5A polymorphisms in HCV genotype 1b pre-treatment serum samples from Estonian patients and their effect on the treatment response. PATIENTS AND METHODS Twenty-nine complete NS5A sequences obtained from patients with chronic HCV-1b infection who had received combined therapy with PegIFNα-2a/RBV were analyzed and compared with the prototype strain HCV-J. Twelve patients achieved a sustained virological response (SVR), 15 were non-SVR and 2 patients stopped treatment because of side effects. RESULTS No significant difference in total number of amino acid mutations was observed between isolates from SVR and non-SVR patients in any known regions of the NS5A protein. However, specific amino acid substitutions at positions 1989 and 2283 correlated significantly with SVR, mutations at positions 1979, 2107, 2171 and 2382 were associated with non-response to treatment and amino acid substitution at position 2319 was observed in relapsers. At phylogenetic analysis, NS5A nucleotide sequences have been subdivided into four groups characterized by the different treatment response. Twenty-four novel nucleotide polymorphisms and 11 novel amino acid polymorphisms were identified based on the phylogenetic tree topology. CONCLUSIONS Specific amino acid substitutions correlating with the treatment response were found. Polymorphisms revealed by phylogenetic analysis may define the signature patterns for treatment susceptible and treatment resistant strains prevalent in Estonia.
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Affiliation(s)
- Tatiana Kuznetsova
- Department of Virology, National Institute for Health Development, Tallinn, Estonia
| | - Tatjana Tallo
- Department of Virology, National Institute for Health Development, Tallinn, Estonia
- Department of Diagnostics and Vaccine, Unit for Molecular Typing, Swedish Institute for Communicable Disease Control, Stockholm, Sweden
| | - Vadim Brjalin
- Department of Internal Medicine, West-Tallinn Central Hospital, Tallinn, Estonia
- Corresponding Author: Vadim Brjalin, Department of Internal Medicine, West-Tallinn Central Hospital, Paldiski Road 68, 10617, Tallinn, Estonia. Tel: +372-6511472, Fax: +372-6511472, E-mail:
| | - Irina Reshetnjak
- Department of Virology, National Institute for Health Development, Tallinn, Estonia
| | - Riina Salupere
- Department of Internal Medicine, University of Tartu, Tartu, Estonia
| | - Ljudmilla Priimagi
- Department of Virology, National Institute for Health Development, Tallinn, Estonia
| | - Olga Katargina
- Department of Virology, National Institute for Health Development, Tallinn, Estonia
| | - Maria Smirnova
- Department of Hemorrhagic Fevers and Pilot Projects, Federal State Budgetary Institution “Chumakov Institute of Poliomyelitis and Viral Encephalitides” of RAMS, Moscow, Russia
| | - Juris Jansons
- Protein Engineering Department, Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Valentina Tefanova
- Department of Virology, National Institute for Health Development, Tallinn, Estonia
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Mansoor A, Ali L, Sabah NU, Hashmi AH, Khan MH, Kazmi SAR, Ahmad N, Siddiqi S, Khan KM. Study of PKRBD in HCV genotype 3a infected patients in response to interferon therapy in Pakistani population. Virol J 2013; 10:352. [PMID: 24321105 PMCID: PMC4029318 DOI: 10.1186/1743-422x-10-352] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 12/02/2013] [Indexed: 12/17/2022] Open
Abstract
Background Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma and infects about 3% world population. Response to interferon therapy depends upon the genotype of the virus and factors associated with the host. Despite a good response to interferon therapy, a considerable number of genotype 3a infected patients remains unalleviated. Results In total forty-nine patients including twenty-five non-responders (non-SVR) and twenty-four responders (SVR) were recruited. Patients were tested for viral status at different intervals and the isolated RNA was sequenced for the NS5A region in both groups. The comparison of PKRBD of HCV between the SVR and non-SVR patients did not confirm any significant difference in the number of mutations. However, when the sequence downstream to the PKRBD of NS5A was compared, two important statistically significant mutations were observed; at positions 2309 (Ala to Ser) and 2326 (Gly to Ala). These mutations were then analysed for tertiary protein structure and important structural changes were observed. Statistically significant difference was also observed when age groups of patients were compared; younger patients showed better response than the older ones. Conclusions The region between PKRBD and IRRDR may be important for prediction of response to IFN therapy for genotype 3a. ISDR and PKRBD have not shown any involvement in treatment response. Further functional analyses of these findings can help in understanding the involvement of the NS5A region in interferon treatment of HCV-3a infected patients.
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Affiliation(s)
- Atika Mansoor
- Institute of Biomedical and Genetic Engineering, 24-Mauve area, G-9/1, Islamabad 44000, Pakistan.
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Sugimoto K, Kim SR, El-Shamy A, Imoto S, Fujioka H, Kim KI, Tanaka Y, Yano Y, Kim SK, Hasegawa Y, Fujinami A, Ohta M, Hatae T, Hotta H, Hayashi Y, Kudo M. Outcome of double-filtration plasmapheresis plus interferon treatment in nonresponders to pegylated interferon plus ribavirin combination therapy. Dig Dis 2013; 31:434-439. [PMID: 24281017 DOI: 10.1159/000355241] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVES We assessed the outcome of double-filtration plasmapheresis (DFPP) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients infected with hepatitis C virus (HCV)-1b whose HCV had not disappeared during PEG-IFN/RBV combination therapy, or who had relapsed after the end of the therapy. Additionally, we investigated factors predictive of sustained virological response (SVR), including host and viral genetic factors, to DFPP plus IFN/RBV therapy. METHODS A total of 40 patients infected with HCV-1b whose HCV virus had not been eradicated by previous PEG-IFN/RBV therapy were enrolled for treatment by DFPP plus IFN/RBV. Rapid virological response (RVR) and SVR were assessed, and pretreatment factors associated with SVR - the interleukin (IL)28B gene, the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR) - were analyzed. RESULTS Of the 40 patients, 9 (23%) achieved RVR and 10 (25%) achieved SVR. The significant factors associated with SVR were IL28B major and RVR, as assessed by multivariate analysis (p = 0.0182, p = 0.0005). CONCLUSION Patients whose HCV is not eradicated by previous PEG-IFN/RBV would be good candidates for combined DFPP and IFN/RBV retreatment provided they demonstrate IL28B major and have achieved RVR.
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Affiliation(s)
- Kayo Sugimoto
- Department of Pharmacy, Kobe Asahi Hospital, Kobe, Japan
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30
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Kim SR, El-Shamy A, Imoto S, Kim KI, Sugimoto K, Kim SK, Tanaka Y, Hatae T, Hasegawa Y, Fujinami A, Ohta M, Hotta H, Kudo M. Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotypes 2a and 2b and high viral load. Dig Dis 2013; 31:426-433. [PMID: 24281016 DOI: 10.1159/000355381] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE We investigated the impact of host genetics represented by the single nucleotide polymorphism (SNP) of the IL28B gene and viral genetic variations within the nonstructural protein 5A (NS5A) [including the interferon (IFN)/ribavirin (RBV) resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR)] on the outcome of pegylated IFN and RBV (PEG-IFN/RBV) treatment. METHODS Sixty-six patients infected with hepatitis C virus (HCV)-2a or HCV-2b who received PEG-IFN/RBV for 24 weeks were examined. RESULTS In HCV-2a, the major genotype of IL28B SNP showed a tendency toward association with sustained virological response (SVR) and rapid virological response (RVR), and four or more mutations in IRRDR (IRRDR[2a] ≥4) and one or more mutations in ISDR plus its carboxyl-flanking region (ISDR/+C[2a] ≥1) were significantly associated with SVR and RVR. In HCV-2b, one or more mutations in the N-terminal part of IRRDR (IRRDR/N[2b] ≥1) were significantly associated with RVR. Multivariate analysis identified the major genotype of IL28B SNP and IRRDR[2a] ≥4 as independent predictive factors of SVR in HCV-2a, with IRRDR[2a] ≥4 being more powerful than the IL28B SNP. Also, IRRDR[2a] ≥4 in HCV-2a and IRRDR/N[2b] ≥1 in HCV-2b were significant determiners of RVR. CONCLUSION The NS5A sequence heterogeneity and IL28B SNP are useful factors to predict the sensitivity to PEG-IFN/RBV therapy in HCV-2a and HCV-2b infections.
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Affiliation(s)
- Soo Ryang Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Japan
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31
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Sugimoto K, Kim SR, El-Shamy A, Imoto S, Ando K, Kim KI, Tanaka Y, Yano Y, Kim SK, Hasegawa Y, Fujinami A, Ohta M, Takashi H, Hotta H, Hayashi Y, Kudo M. Factors of response to pegylated interferon/ribavirin combination therapy and mechanism of viral clearance. Dig Dis 2013; 31:421-425. [PMID: 24281015 DOI: 10.1159/000355239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVES This study explores viral factors of the interferon (IFN) and ribavirin (RBV) resistance-determining region (IRRDR), the IFN sensitivity-determining region (ISDR) and the core protein, and host factor interleukin 28B associated with response to pegylated IFN (PEG-IFN) and RBV combination therapy, and the correlation of viral and host factors with IFN-λ1. METHODS A total of 58 patients underwent PEG-IFN/RBV combination therapy for 48 weeks. The pretreatment factors associated with rapid virological response (RVR) and sustained virological response (SVR) were analyzed. Pretreatment IFN-λ1 serum levels were compared with the viral and host factors. RESULTS Univariate analysis showed that IRRDR ≥6 and ISDR ≥2 were significant pretreatment predictors of RVR, and multivariate analysis identified IRRDR ≥6 and hemoglobin as significant predictors of SVR. Pretreatment IFN-λ1 was significantly higher in the SVR group than in the non-SVR group and also in the IRRDR ≥6 group than in the IRRDR ≤5 group. CONCLUSIONS IRRDR ≥6 was the only significant predictor of SVR and was correlated with IFN-λ1. High serum levels of IFN-λ1 may be conducive to effective PEG-IFN/RBV combination therapy because of the immunomodulatory system.
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Affiliation(s)
- Kayo Sugimoto
- Department of Pharmacy, Kobe Asahi Hospital, Kobe, Japan
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Utility of detection of telaprevir-resistant variants for prediction of efficacy of treatment of hepatitis C virus genotype 1 infection. J Clin Microbiol 2013; 52:193-200. [PMID: 24197875 DOI: 10.1128/jcm.02371-13] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir-peginterferon (PEG-IFN)-ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of <1.3 μg/kg of body weight, an IL28B rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of <5,000/mm(3) as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment.
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Schweitzer CJ, Liang TJ. Impact of host and virus genome variability on HCV replication and response to interferon. Curr Opin Virol 2013; 3:501-7. [PMID: 23835049 PMCID: PMC3797205 DOI: 10.1016/j.coviro.2013.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 06/05/2013] [Accepted: 06/10/2013] [Indexed: 02/07/2023]
Abstract
Since the discovery of hepatitis C virus (HCV), treatment has proven difficult and the regimen of pegylated interferon-α and ribavirin is only effective for half of patients. Evidence suggests that host and viral genome variations play a role in either viral clearance or persistence. Powerful genomic technologies have made it possible to study genome-wide associations with treatment response, which yielded critical genetic polymorphisms that predict treatment response. This has important implications for treatment of HCV infection and opened the door to the possibility of genetic marker-guided treatment (personalized medicine). This review will focus on the recent advances in understanding host and viral genetic variations with regards to treatment and the importance for future therapeutic intervention.
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Affiliation(s)
- Cameron J Schweitzer
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
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Akuta N, Suzuki F, Seko Y, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Hara T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1. J Med Virol 2013; 85:1028-36. [PMID: 23588728 DOI: 10.1002/jmv.23579] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2013] [Indexed: 12/11/2022]
Abstract
Using ultra-deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir-resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG-IFN)/ribavirin could be predicted at baseline in previous non-responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG-IFN/ribavirin, received a 24-week regimen of triple therapy, and were evaluated for appearance of telaprevir-resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra-deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG-IFN/ribavirin) than in other patients. Telaprevir-resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra-deep sequencing. The appearance of telaprevir-resistant variants was examined by ultra-deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re-elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir-resistant variants after commencement of triple therapy in prior non-responders of HCV genotype 1, even with the use of ultra-deep sequencing.
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Affiliation(s)
- Norio Akuta
- Department of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
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Rajyaguru S, Yang H, Martin R, Miller MD, Mo H. Development and characterization of a replicon-based phenotypic assay for assessing HCV NS4B from clinical isolates. Antiviral Res 2013; 100:328-36. [PMID: 24013002 DOI: 10.1016/j.antiviral.2013.08.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 08/23/2013] [Accepted: 08/25/2013] [Indexed: 01/10/2023]
Abstract
The hepatitis C virus (HCV) NS4B inhibitors have shown potent inhibition of HCV replication in vitro. To assess the effect of viral diversity on the susceptibility to NS4B inhibitors, genotype (GT)-specific GT1a and GT1b replicon shuttle vectors were designed and created for cloning HCV NS4B genes from clinical isolates. For the GT1b NS4B shuttle vector, the S2204I adaptive mutation was introduced in NS5A to improve replication due to the replacement of the K1846T adaptive mutation in NS4B with NS4B from the clinical isolates. In addition to the adaptive mutations, a newly identified Huh-7 cell line, Huh-7-1C, which is highly permissive for both GT1a and GT1b replication, was used to further enhance the replication levels. HCV NS4B gene from clinical isolates was amplified and inserted into the corresponding GT1a and GT1b modified lab strain chimeric replicons. GT1a and GT1b chimeric replicons expressing diverse NS4B genes from corresponding subtypes of clinical isolates replicated at highly efficient levels for phenotypic analysis. Due to natural variation in their amino acid residues in NS4B, these isolates displayed varying drug susceptibilities to an NS4B inhibitor. In mixed populations with wild-type, the sensitivity of resistance detection of NS4B resistant mutants H94R and V105M was between 20% and 80%. The chimeric shuttle vectors can be used to characterize the activity of antiviral drugs targeting NS4B from diverse natural clinical isolates and aid in the development of novel compounds against HCV NS4B.
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Affiliation(s)
- Sonal Rajyaguru
- Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA 94404, United States
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36
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Sede M, Laufer N, Ojeda D, Gun A, Cahn P, Quarleri J. Analysis of sequences of hepatitis C virus NS5A genotype 1 in HIV-coinfected patients with a null response to nitazoxanide or peg-interferon plus ribavirin. Arch Virol 2013; 158:1907-1915. [PMID: 23553458 DOI: 10.1007/s00705-013-1687-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 02/22/2013] [Indexed: 02/06/2023]
Abstract
Even though new drugs have been approved for treatment of hepatitis C virus (HCV) infection, the risk of drug-drug interactions and concern about overlapping toxicities has hindered the development of studies in HIV/HCV-coinfected individuals. Traditional treatment with pegylated interferon plus ribavirin (peg-IFN + RBV) is very expensive and has a low rate of sustained virological response in coinfected patients, especially if they are infected with HCV genotype 1. Nitazoxanide (NTZ) is a drug that is being evaluated for the treatment of chronic HCV infection, both in HCV-monoinfected and HIV/HCV-coinfected patients. Understanding the NTZ resistance mechanism could allow the development of resistance to be minimized and would expand the treatment options, mainly in special populations such as HIV/HCV-coinfected patients. Similarly to IFN, NTZ increases the activity of the cellular protein kinase activated by double-stranded RNA (PKR), a key kinase in the innate antiviral response. In order to elucidate whether sequence heterogeneity in the PKR-binding domain of HCV NS5A genotype 1 could influence the antiviral activity of either NTZ monotherapy or peg-IFN + RBV, baseline and end-of-therapy plasma samples from two groups of eleven non-responder HIV/HCV-coinfected patients that had received NTZ or peg-IFN + RBV were studied. Most of the HCV NS5A sequences examined at the end of therapy did not change from the baseline, even after 30 days course of antiviral therapy. An extensive comparison of HCV NS5A genotype 1 and 4 sequences from the database with reported IFN therapy outcome was performed in order to infer their phylogenetic relationships. The HCV genotype 1 NS5A nucleotide sequences from therapy-non-responder patients were intermingled amongst those from the database, irrespective of their IFN-therapy outcome. When comparing NS5A-PKRBD amino acid sequences, significant differences were observed in genotype 4, but not in genotype 1 (p < 0.0001 and p > 0.05, respectively). In conclusion, despite IFN and NTZ sharing the protein kinase activated by double-stranded RNA as their cellular target, the HCV genotype 1 strategy to counteract the IFN action mediated by NS5A ISDR/PKRBD does not explain drug resistance in HIV/HCV-coinfected patients. Other viral factors that are possibly involved are discussed as well.
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Affiliation(s)
- M Sede
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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Sharma SD. Hepatitis C virus 1b viral factors (core, NS3, and NS5A) and increased risk of hepatocellular carcinoma. Hepatology 2013; 58:491-3. [PMID: 23471816 DOI: 10.1002/hep.26362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Revised: 02/19/2013] [Accepted: 02/26/2013] [Indexed: 12/24/2022]
Affiliation(s)
- Suresh D. Sharma
- Department of Biochemistry and Molecular Biology; , Pennsylvania State University University Park; PA
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38
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El-Shamy A, Shindo M, Shoji I, Deng L, Okuno T, Hotta H. Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate with development of hepatocellular carcinoma. Hepatology 2013; 58:555-63. [PMID: 23281009 DOI: 10.1002/hep.26205] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 12/09/2012] [Indexed: 12/13/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is one of the common sequelae of hepatitis C virus (HCV) infection. It remains controversial, however, whether HCV itself plays a direct role in the development of HCC. Although HCV core, NS3, and NS5A proteins were reported to display tumorigenic activities in cell culture and experimental animal systems, their clinical impact on HCC development in humans is still unclear. In this study we investigated sequence polymorphisms in the core protein, NS3, and NS5A of HCV genotype 1b (HCV-1b) in 49 patients who later developed HCC during a follow-up of an average of 6.5 years and in 100 patients who did not develop HCC after a 15-year follow-up. Sequence analysis revealed that Gln at position 70 of the core protein (core-Gln(70) ), Tyr at position 1082 plus Gln at 1112 of NS3 (NS3-Tyr(1082) /Gln(1112) ), and six or more mutations in the interferon/ribavirin resistance-determining region of NS5A (NS5A-IRRDR≥6) were significantly associated with development of HCC. Multivariate analysis identified core-Gln(70) , NS3-Tyr(1082) /Gln(1112) , and α-fetoprotein (AFP) levels (>20 ng/L) as independent factors associated with HCC. Kaplan-Meier analysis revealed a higher cumulative incidence of HCC for patients infected with HCV isolates with core-Gln(70) , NS3-Tyr(1082) /Gln(1112) or both than for those with non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) ). In most cases, neither the residues at position 70 of the core protein nor positions 1082 and 1112 of the NS3 protein changed during the observation period. CONCLUSION HCV isolates with core-Gln(70) and/or NS3-Tyr(1082) /Gln(1112) are more closely associated with HCC development compared to those with non-(Gln(70) plus NS3-Tyr(1082) /Gln(1112) ).
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Affiliation(s)
- Ahmed El-Shamy
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
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Khaliq S, Latief N, Jahan S. Role of different regions of the hepatitis C virus genome in the therapeutic response to interferon-based treatment. Arch Virol 2013; 159:1-15. [PMID: 23851652 DOI: 10.1007/s00705-013-1780-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 05/28/2013] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) is considered a significant risk factor in HCV-induced liver diseases and development of hepatocellular carcinoma (HCC). Nucleotide substitutions in the viral genome result in its diversification into quasispecies, subtypes and distinct genotypes. Different genotypes vary in their infectivity and immune response due to these nucleotide/amino acid variations. The current combination treatment for HCV infection is pegylated interferon α (PEG-IFN-α) with ribavirin, with a highly variable response rate mainly depending upon the HCV genotype. Genotypes 2 and 3 are found to respond better than genotypes 1 and 4, which are more resistant to IFN-based therapies. Different studies have been conducted worldwide to explore the basis of this difference in therapy response, which identified some putative regions in the HCV genome, especially in Core and NS5a, and to some extent in the E2 region, containing specific sequences in different genotypes that act differently with respect to the IFN response. In the review, we try to summarize the role of HCV proteins and their nucleotide sequences in association with treatment outcome in IFN-based therapy.
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Affiliation(s)
- Saba Khaliq
- Department of Immunology, University of Health Sciences, Lahore, Pakistan,
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Prediction of treatment efficacy and telaprevir-resistant variants after triple therapy in patients infected with hepatitis C virus genotype 1. J Clin Microbiol 2013; 51:2862-8. [PMID: 23784126 DOI: 10.1128/jcm.01129-13] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
It is often difficult to predict the response to telaprevir-pegylated interferon (PEG-IFN)-ribavirin triple therapy and the appearance of telaprevir-resistant variants. The present study determined the predictive factors of a sustained virological response (SVR) to 12- or 24-week triple therapy (T12PR12 or T12PR24, respectively) in 194 Japanese patients infected with hepatitis C virus genotype 1b (HCV-1b). The study also evaluated whether ultradeep sequencing technology can predict at baseline the emergence of resistant variants after the start of therapy. Analysis of the data of the entire group indicated that an SVR was achieved in 78% of the patients. Multivariate analysis identified IL28B rs8099917 (genotype TT), the substitution of amino acid (aa) 70 (Arg70), response to prior treatment (naive or relapse), PEG-IFN dose (≥ 1.3 μg/kg of body weight), and treatment regimen (T12PR24) as significant determinants of SVR. Among patients of the T12PR24 group, 92% with genotype TT achieved an SVR, irrespective of a substitution at aa 70. In patients with the non-TT genotype, an SVR was achieved in 76% of those with Arg70, while only 14% of patients with the non-TT genotype, Gln70(His70), and nonresponse to ribavirin combination therapy achieved an SVR. Ultradeep sequencing was conducted for 17 patients who did not achieve an SVR to determine the emergence of resistant variants during therapy. De novo resistant variants were detected in 16 of 17 patients (94%), regardless of the variant frequencies detected at baseline. In conclusion, the results indicate that the response to triple therapy can be predicted by the combination of host, viral, and treatment factors and that it is difficult to predict at baseline the telaprevir-resistant variants that emerge during triple therapy, even with the use of ultradeep sequencing.
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Hayashi K, Katano Y, Masuda H, Ishizu Y, Kuzuya T, Honda T, Ishigami M, Itoh A, Hirooka Y, Nakano I, Ishikawa T, Urano F, Yoshioka K, Toyoda H, Kumada T, Goto H. Pegylated interferon monotherapy in patients with chronic hepatitis C with low viremia and its relationship to mutations in the NS5A region and the single nucleotide polymorphism of interleukin-28B. Hepatol Res 2013; 43:580-588. [PMID: 23356752 DOI: 10.1111/hepr.12005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Revised: 10/08/2012] [Accepted: 10/15/2012] [Indexed: 02/08/2023]
Abstract
AIM Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus (HCV) level have a high sustained virological response (SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon (PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region (ISDR) and the single-nucleotide polymorphism (SNP) of interleukin-28B (IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. METHODS One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/mL or less. RESULTS SVR was achieved in 94 patients (92.2%). HCV levels (≤50 KIU/mL) and ISDR (≥2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy (P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR (P = 0.004). CONCLUSION The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels.
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Affiliation(s)
- Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya
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Response of hepatitis C virus to long-term passage in the presence of alpha interferon: multiple mutations and a common phenotype. J Virol 2013; 87:7593-607. [PMID: 23637397 DOI: 10.1128/jvi.02824-12] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Cell culture-produced hepatitis C virus (HCV) has been subjected to up to 100 serial passages in human hepatoma cells in the absence or presence of different doses of alpha interferon (IFN-α). Virus survival, genetic changes, fitness levels, and phenotypic traits have been examined. While high initial IFN-α doses (increasing from 1 to 4 IU/ml) did not allow HCV survival beyond passage 40, a gradual exposure (from 0.25 to 10 IU/ml) allowed the virus to survive for at least 100 passages. The virus passaged in the presence of IFN-α acquired IFN-α resistance as evidenced by enhanced progeny production and viral protein expression in an IFN-α environment. A partial IFN-α resistance was also noted in populations passaged in the absence of IFN-α. All lineages acquired adaptative mutations, and multiple, nonsynonymous mutations scattered throughout the genome were present in IFN-α-selected populations. Comparison of consensus sequences indicates a dominance of synonymous versus nonsynonymous substitutions. IFN-α-resistant populations displayed decreased sensitivity to a combination of IFN-α and ribavirin. A phenotypic trait common to all assayed viral populations is the ability to increase shutoff host cell protein synthesis, accentuated in infections with IFN-α-selected populations carried out in the presence of IFN-α. The trait was associated with enhanced phosphorylation of protein kinase R (PKR) and eIF2α, although other contributing factors are likely. The results suggest that multiple, independent mutational pathways can confer IFN-α resistance to HCV and might explain why no unified picture has been obtained regarding IFN-α resistance in vivo.
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43
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Ueda Y, Kaido T, Ogura Y, Ogawa K, Yoshizawa A, Hata K, Fujimoto Y, Miyagawa-Hayashino A, Haga H, Marusawa H, Teramukai S, Uemoto S, Chiba T. Pretransplant serum hepatitis C virus RNA levels predict response to antiviral treatment after living donor liver transplantation. PLoS One 2013; 8:e58380. [PMID: 23505497 PMCID: PMC3591322 DOI: 10.1371/journal.pone.0058380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 02/04/2013] [Indexed: 12/24/2022] Open
Abstract
Background Given the limited efficacy and high adverse event rate associated with treatment of recurrent hepatitis C after liver transplantation, an individualized treatment strategy should be considered. The aim of this study was to identify predictors of response to antiviral therapy for hepatitis C after living donor liver transplantation (LDLT) and to study the associated adverse events. Methods A retrospective chart review was performed on 125 hepatitis C virus (HCV)-positive LDLT recipients who received interferon plus ribavirin and/or peginterferon plus ribavirin therapy at Kyoto University between January 2001 and June 2011. Results Serum HCV RNA reached undetectable levels within 48 weeks in 77 (62%) of 125 patients, and these patients were defined as showing virological response (VR). Of 117 patients, 50 (43%) achieved sustained VR (SVR). Predictive factors associated with both VR and SVR by univariate analysis included low pretransplant serum HCV RNA levels, a non-1 HCV genotype, and low pretreatment serum HCV RNA levels. In addition, LDLT from ABO-mismatched donors was significantly associated with VR, and white cell and neutrophil counts before interferon therapy were associated with SVR. Multivariate analysis showed that 2 variables–pretransplant serum HCV RNA level less than 500 kIU/mL and a non-1 HCV genotype–remained in models of both VR and SVR and that an ABO mismatch was associated with VR. No variables with a significant effect on treatment withdrawal were found. Conclusions Virological response to antiviral therapy in patients with hepatitis C recurring after LDLT can be predicted prior to transplant, based on pretransplant serum HCV-RNA levels and HCV genotype. LDLT from ABO-mismatched donors may contribute to more efficacious interferon therapy. Trial Registration UMIN-CTR
UMIN000003286
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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El Awady MK, Bader El Din NG, Tabll A, El Hosary Y, Abdel Aziz AO, El Khayat H, Salama M, Abdelhafez TH. IL28B polymorphism and cytomegalovirus predict response to treatment in Egyptian HCV type 4 patients. World J Gastroenterol 2013; 19:290-298. [PMID: 23345953 PMCID: PMC3547570 DOI: 10.3748/wjg.v19.i2.290] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Revised: 04/28/2012] [Accepted: 05/05/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To test whether the status of positive cytomegalovirus (CMV) DNA detection adds to the predictive value of IL28B and to further categorize C/T allele carriers. METHODS This study included 166 chronic hepatitis C (CHC) patients who received combined interferon and ribavirin therapy for 48 wk, 84 spontaneous hepatitis C virus (HCV) resolvers who were positive for IgG anti-HCV antibody and negative for HCV RNA, and 100 healthy subjects who were negative for both HCV antibodies and RNA as controls. Genomic DNA from peripheral blood was used for IL28B rs.12979860 single nucleotide polymorphism (SNP) and CMV DNA detection. A 139 bp fragment containing IL28B SNP was amplified in all subjects by polymerase chain reaction using a specifically designed primer. Then the IL28B rs.12979860 SNP was detected by restriction fragment length polymorphism (RFLP) genotyping. The presence of CMV DNA was tested by amplification of the gB1 gene using nested polymerase chain reaction. The role of CMV and IL28B rs.12979860 SNP genotypes in determining the response rate to combined interferon therapy and clinical status of patients were statistically analyzed. RESULTS Current data showed that 67% of patients carrying the IL28B 12979860 C/C allele had a sustained viral response (SVR) while the genotypes C/T and TT were associated with lower SVR rates, 50% and 48%, respectively. SVR rates for the C/C allele were lower than other HCV genotypes and/or other populations. Genotype CC was associated with the response to interferon (P = 0.025). Genotype C/C was reduced from 48% in controls to 14% in CHC patients suggesting its protective role against progression to chronicity. The majority of spontaneously cleared subjects (86%) were C/C, confirming its protective role. The C/T allele was present in 71% of CHC patients compared with 38% of controls, so the use of IL28B SNP genotyping only in these patients may be of little value as a predictor of response. CMV reactivation occurred in 40% of CHC patients. Co-infection with CMV seriously diminished the response to interferon (IFN) therapy, with SVR rates in C/C genotypes 87.5% in CMV-negative patients and 12.5% in CMV-positive patients (P < 0.0001). SVR rates among C/T carriers were reduced to < 50% in patients with positive CMV DNA while the non-response rate doubled. These data indicate that a supplemental assay for CMV viremia adds to the prognostic value of IL28B genotyping. CONCLUSION The results suggest that both genetic (i.e., spontaneous) and therapeutic (IFN-based therapy) arms are complementary in the battle against HCV. CMV DNA testing may be of value to better predict the response to IFN, particularly in IL28B C/T carriers.
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Affiliation(s)
- Mostafa K El Awady
- Department of Microbial Biotechnology, National Research Center, Cairo, Giza 12622, Egypt.
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45
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Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res 2013; 43:1-34. [PMID: 23332085 DOI: 10.1111/hepr.12020] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
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- Department of Gastroenterology and Hepatology, Faculty of Medicine, Tokyo Medical and Dental University
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46
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Kozuka R, Enomoto M, Hai H, Ogawa T, Nakaya M, Hagihara A, Fujii H, Kobayashi S, Iwai S, Morikawa H, Tamori A, Kawada N. Changes in sequences of core region, interferon sensitivity-determining region and interferon and ribavirin resistance-determining region of hepatitis C virus genotype 1 during interferon-alpha and ribavirin therapy, and efficacy of retreatment. Hepatol Res 2012; 42:1157-1167. [PMID: 22672644 DOI: 10.1111/j.1872-034x.2012.01046.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIM Some regions associated with sensitivity to interferon-α and ribavirin have been identified in the hepatitis C virus (HCV) genome, including amino acid 70 in the core region (core a.a. 70), a.a. 2209-2248 (interferon sensitivity-determining region, ISDR) and a.a. 2334-2379 (interferon and ribavirin resistance-determining region, IRRDR). METHODS We examined changes in the sequences of these regions in 25 patients with chronic HCV genotype 1 infection who had not had sustained virological response (SVR) to interferon-α and ribavirin for 24-48 weeks and subsequently received retreatment for 48-72 weeks. RESULTS At baseline, the core a.a. 70 was mutant (resistant) type in seven patients. At the start of retreatment, the core a.a. 70 had changed from sensitive to resistant type in 2 patients, and SVR was not achieved by retreatment. The ISDR variations were resistant type (0-1 mutations) in 17 patients at baseline. After 2 weeks of treatment, amino acid change was found in two patients; in one, the substitutions returned to baseline status after treatment, and in the other, the substitution persisted. At the start of retreatment, ISDR sequences had changed from resistant to sensitive type in two patients and SVR was achieved and from sensitive to resistant type in three patients and SVR was not achieved. The IRRDR variations were resistant type (<6 mutations) in 19 patients at baseline and at the start of retreatment. CONCLUSION Sequences of the core region and ISDR sometimes change during anti-HCV therapy, potentially affecting the outcomes of retreatment.
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Affiliation(s)
- Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka Center for the Advancement of Higher Education, Faculty of Engineering, Kinki University, Hiroshima, Japan
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Torti C, Zazzi M, Abenavoli L, Trapasso F, Cesario F, Corigliano D, Cosco L, Costa C, Curia RL, De Rosa M, Foti G, Giraldi C, Leone R, Liberto MC, Lucchino D, Marascio N, Masciari R, Matera G, Pisani V, Serrao N, Surace L, Zicca E, Castelli F, Ciccozzi M, Puoti M, Focà A. Future research and collaboration: the "SINERGIE" project on HCV (South Italian Network for Rational Guidelines and International Epidemiology). BMC Infect Dis 2012; 12 Suppl 2:S9. [PMID: 23173812 PMCID: PMC3495626 DOI: 10.1186/1471-2334-12-s2-s9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology) project is intended to set up a collaborative network comprising virologists, clinicians and public health officials dealing with patients affected by HCV disease in the Calabria Region. A prospective observational data-base of HCV infection will be developed and used for studies on HCV natural history, response to treatment, pharmaco-economics, disease complications, and HCV epidemiology (including phylogenetic analysis). With this approach, we aim at improving the identification and care of patients, focusing on upcoming research questions. The final objective is to assist in improving care delivery and inform Public Health Authorities on how to optimize resource allocation in this area.
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Affiliation(s)
- C Torti
- Unit of Infectious Diseases, University Magna Graecia, Catanzaro, Italy.
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Maekawa S, Sakamoto M, Miura M, Kadokura M, Sueki R, Komase K, Shindo H, Komatsu N, Shindo K, Kanayama A, Ohmori T, Amemiya F, Takano S, Yamaguchi T, Nakayama Y, Kitamura T, Inoue T, Okada S, Enomoto N. Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection. Hepatology 2012; 56:1611-21. [PMID: 22577043 DOI: 10.1002/hep.25826] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED To comprehensively characterize the contribution of virological factors as well as interleukin-28B (IL28B) single-nucleotide polymorphisms (SNPs) in determining treatment responses in pegylated-interferon plus ribavirin (Peg-IFN/RBV) therapy for chronic hepatitis C virus (HCV)-1b infection, we undertook a retrospective cohort analysis for the pretreatment dominant complete HCV open reading frame (ORF) amino-acid (aa) sequence study in 103 consecutive HCV-1b Japanese patients. The dominant HCV sequences classified by the response were subjected to systematic sliding-window comparison analysis to characterize response-specific viral sequences, along with IL28B SNP analyses (rs8099917). In each comparison of the patients between with and without rapid viral response (RVR), nonearly viral response (nEVR), sustained virological response (SVR), or relapse, the following regions were extracted as most significantly associated with the different responses respectively: nonstructural protein 5A (NS5A) aa.2224-2248 (P = 1.2E-07); core aa.70 (P = 4E-04); NS5A aa.2340-2382 (P = 7.0E-08); and NS5A aa.2360-2377 (P = 1.1E-05). Those NS5A regions nearly coincided with the interferon (IFN) sensitivity-determining region (NS5A aa.2209-2248) and the IFN/RBV resistance-determining region (NS5A aa.2339-2379). In a multivariate analysis, the IL28B SNP (odds ratio [OR] = 16.8; P = 0.009) and NS5A aa.2340-2382 (OR = 13.8; P = 0.0003) were extracted as the two most-significant independent variables contributing to the final outcome. CONCLUSION In Peg-IFN/RBV therapy, polymorphisms in IL28B, NS5A aa.2224-2248, core aa.70, and, most important, NS5A aa.2340-2382 have a tremendous influence on treatment response in association with viral kinetics, resulting in significantly different outcomes in chronic HCV-1b infection.
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Affiliation(s)
- Shinya Maekawa
- Department of Advanced Medicine for Liver Diseases, University of Yamanashi, Yamanashi, Japan.
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Kim SR, El-Shamy A, Imoto S, Kim KI, Ide YH, Deng L, Shoji I, Tanaka Y, Hasegawa Y, Ota M, Hotta H. Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotype 1b and high viral load. J Gastroenterol 2012; 47:1143-1151. [PMID: 22441534 DOI: 10.1007/s00535-012-0578-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Accepted: 02/27/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study explores pretreatment predictive factors for ultimate virological responses to pegylated interferon-α (1.5 μg/kg/week) and ribavirin (600-1000 mg/day) (PEG-IFN/RBV) combination therapy for patients infected with hepatitis C virus (HCV)-1b and a high viral load. METHODS A total of 75 patients underwent PEG-IFN/RBV combination therapy for 48 weeks. HCV amino acid (aa) substitutions in non-structural protein 5a, including those in the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region and the core regions, as well as the genetic variation (rs8099917) near the interleukin 28B (IL28B) gene (genotype TT) were analyzed. RESULTS Of the 75 patients, 49 % (37/75) achieved a sustained virological response (SVR), 27 % (20/75) showed relapse, and 24 % (18/75) showed null virological response (NVR). Multivariate logistic regression analysis identified IRRDR with 6 or more mutations (IRRDR ≥6) [odds ratio (OR) 11.906, p < 0.0001] and age <60 years (OR 0.228, p = 0.015) as significant determiners of SVR and IL28B minor (OR 14.618, p = 0.0019) and platelets <15 × 10(4)/mm(3) (OR 0.113, p = 0.0096) as significant determiners of NVR. A combination of IRRDR ≥6 and age <60 years improved SVR predictability (93.3 %), and that of IRRDR ≤5 and age ≥60 years improved non-SVR predictability (84.0 %). Similarly, a combination of IL28B minor and platelets <15 × 10(4)/mm(3) improved NVR predictability (85.7 %), and that of IL28B major and platelets ≥15 × 10(4)/mm(3) improved non-NVR (response) (97.1 %) predictability. CONCLUSION IRRDR ≥6 and age <60 years were significantly associated with SVR. IL28B minor and platelets <15 × 10(4)/mm(3) were significantly associated with NVR. Certain combinations of these factors improved SVR and NVR predictability and could, therefore, be used to design therapeutic strategies.
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Affiliation(s)
- Soo Ryang Kim
- Department of Gastroenterology, Kobe Asahi Hospital, 3-5-25 Bououji-cho, Nagata-ku, Kobe 653-0801, Japan.
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NS5A sequence heterogeneity of hepatitis C virus genotype 4a predicts clinical outcome of pegylated-interferon-ribavirin therapy in Egyptian patients. J Clin Microbiol 2012; 50:3886-92. [PMID: 22993188 DOI: 10.1128/jcm.02109-12] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus genotype 4 (HCV-4) is the cause of approximately 20% of the 180 million cases of chronic hepatitis C in the world. HCV-4 infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. Viral genetic polymorphisms, especially within core and NS5A regions, have been implicated in influencing the response to pegylated-interferon and ribavirin (PEG-IFN/RBV) combination therapy in HCV-1 infection. However, this has not been confirmed in HCV-4 infection. Here, we investigated the impact of heterogeneity of NS5A and core proteins of HCV-4, mostly subtype HCV-4a, on the clinical outcomes of 43 Egyptian patients treated with PEG-IFN/RBV. Sliding window analysis over the carboxy terminus of NS5A protein identified the IFN/RBV resistance-determining region (IRRDR) as the most prominent region associated with sustained virological response (SVR). Indeed, 21 (84%) of 25 patients with SVR, but only 5 (28%) of 18 patients with non-SVR, were infected with HCV having IRRDR with 4 or more mutations (IRRDR ≥ 4) (P = 0.0004). Multivariate analysis identified IRRDR ≥ 4 as an independent SVR predictor. The positive predictive value of IRRDR ≥ 4 for SVR was 81% (21/26; P = 0.002), while its negative predictive value for non-SVR was 76% (13/17; P = 0.02). On the other hand, there was no significant correlation between core protein polymorphisms, either at residue 70 or at residue 91, and treatment outcome. In conclusion, the present results demonstrate for the first time that IRRDR ≥ 4, a viral genetic heterogeneity, would be a useful predictive marker for SVR in HCV-4 infection when treated with PEG-IFN/RBV.
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