Sequence Heterogeneity in NS5A of Hepatitis C Virus Genotypes 2a and 2b and Clinical Outcome of Pegylated-Interferon/Ribavirin Therapy

El-Shamy, Ahmed; Shoji, Ikuo; Kim, Soo-Ryang; Ide, Yoshihiro; Imoto, Susumu; Deng, Lin; Yoon, Seitetsu; Fujisawa, Takashi; Tani, Satoshi; Yano, Yoshihiko; Seo, Yasushi; Azuma, Takeshi; Hotta, Hak

doi:10.1371/journal.pone.0030513

Cited by 16 publications

(21 citation statements)

References 36 publications

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“…As we can see in Figure 2, the pre-and post-treatment HCV sequences appeared to be almost uniform in three different regions, moreover, the quasispecies variation shrank to be further more simplified after 12 weeks of therapy. The IFN-sensitivity determining region (ISDR) has been discussed and was correlated with IFN responsiveness in HCV genotype 1b and 2a infection (11)(12)(13)(14). But in our study, the population at the 12-week treatment in the region ISDR became more similar to the HCV-JFH1 (Figure 3), an IFN sensitive strain.…”

Section: Evolution Of Hcv Rna After Standard Therapycontrasting

confidence: 52%

Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C

Chen

Wei

et al. 2012

Chin. J. Cancer Res.

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Objective: The combination of interferon (IFN) and ribavirin (RBV) is the standard therapy for hepatitis C virus (HCV) infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet limited.This study aimed to investigate the mechanism of the poor response in a case of HCV genotype 2a infection. Results: The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN.Conclusions: During the course of the chronic infection, HCV population seems to be adapted to the patient's immunological system, and further to be selected by combination of IFN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region (ISDR) of NS5A during chronic infection and IFN/RBV therapy.

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Section: Evolution Of Hcv Rna After Standard Therapycontrasting

confidence: 52%

Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C

Chen

Wei

et al. 2012

Chin. J. Cancer Res.

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“…Correlation between NS5A sequence heterogeneity and SVR in HCV-4 infection. We and other researchers reported significant correlation between sequence polymorphisms within the Cterminal half of NS5A, including that in ISDR and IRRDR, and PEG-IFN/RBV treatment outcome in HCV-1 and HCV-2 infections (13,15,18,30). However, this information is quite limited in HCV-4 infection.…”

Section: Patients' Responses To Peg-ifn/rbv Combination Therapymentioning

confidence: 78%

“…It is also possible that the genetic flexibility of IRRDR is accompanied by compensatory changes elsewhere in the viral genome and that these compensatory changes affect overall viral fitness and responses to IFNbased therapy (8,29,41). Also, it is worth noting that IRRDR is among the most variable sequences across the different genotypes and subtypes of HCV (25) whereas its upstream and downstream sequences show a higher degree of sequence conservation (15). This may suggest that whereas the upstream and downstream sequences have a conserved function(s) across all the HCV genotypes, IRRDR sequences have a genotype-dependent or even a strain-dependent function(s).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, in the era of PEG-IFN/ RBV combination therapy, we identified a new region near the C terminus of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR) (13). Recently, we also demonstrated the correlation between IRRDR polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a and -2b infections (15). In addition, HCV core protein polymorphism, in particular at positions 70 and 91, was also proposed as a pretreatment predictor of poor virological response in patients infected with HCV-1b (4)(5)(6).…”

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confidence: 99%

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NS5A Sequence Heterogeneity of Hepatitis C Virus Genotype 4a Predicts Clinical Outcome of Pegylated-Interferon–Ribavirin Therapy in Egyptian Patients

El-Shamy¹,

Shoji²,

El-Akel³

et al. 2012

J Clin Microbiol

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Hepatitis C virus (HCV) is a major cause of chronic liver disease, hepatocellular carcinoma, and deaths from liver disease and is the most common indication for liver transplantation (7,(26)(27)(28)38). HCV has been classified into seven major genotypes and a series of subtypes (35,36). In general, HCV genotype 4 (HCV-4) is common in the Middle East and Africa, where it is responsible for more than 80% of HCV infections (23). Although HCV-4 is the cause of approximately 20% of the 180 million cases of chronic hepatitis C in the world, it has not been a major subject of research.Egypt has the highest prevalence of HCV worldwide (15%) and the highest prevalence of HCV-4, which is responsible for 90% of the total HCV infections, with a predominance of the subtype 4a (HCV-4a) (1, 32). This extraordinarily high prevalence results in an increasing incidence of hepatocellular carcinoma in Egypt, which is now the second most frequent cause of cancer and cancer mortality among men (17, 21). More than 2 decades have passed since the discovery of HCV, and yet therapeutic options remain limited. Up to 2011, the standard treatment for chronic hepatitis C consisted of pegylated alpha interferon (PEG-IFN) and ribavirin (RBV) (19); however, by May 2011 two protease inhibitors (telaprevir and boceprevir) were approved by the Food and Drug Administration (FDA) for use in combination with PEG-IFN/ RBV for adult chronic hepatitis C patients with HCV genotype 1 (24, 34). Since the approval of these new protease inhibitors for treatment of HCV-1 infection, the response of HCV-4 to the standard regimen of treatment (PEG-IFN/RBV) has lagged behind other genotypes and HCV-4 has become the most resistant genotype to treat. As PEG-IFN/RBV still remains to be used to treat HCV-4-infected patients, exploring the factors that predict the outcome of PEG-IFN/RBV treatment, such as sustained virological response (SVR), for HCV-4 infections is needed to assess more accurately the likelihood of SVR and thus to make more informed treatment decisions.While the SVR rate for PEG-IFN/RBV treatment hovers at 50 to 60% in HCV-1 and -4 infection, it is up to 80% in HCV-2 and -3 infections (19,33). This difference in responses among patients infected with different HCV genotypes suggests that viral genetic heterogeneity could affect, at least to some extent, the sensitivity to IFN-based therapy. In this context, the correlation between IFNbased therapy outcome and sequence polymorphisms within the viral core and NS5A proteins has been widely discussed, in particular in regard to Japanese patients with HCV-1b infection. Initially, in the era of IFN monotherapy, it was proposed that sequence variations within a region in NS5A of HCV-1b, called the IFN sensitivity-determining region (ISDR), were correlated with IFN responsiveness (18). Subsequently, in the era of PEG-IFN/

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“…A high degree (≥ 6) of sequence variation in IRRDR was thought to be a useful marker for predicting SVR, whereas a less diverse (≤ 5) IRRDR sequence predicted non-SVR. In addition, the significance of part of the ISDR plus its carboxy-flanking region (2232-2262) and IRRDR on therapeutic outcome of G2a along with G2b patients has been reported [42].…”

Section: Interferon Ribavirin Resistance-determining Region (Irrdr) Amentioning

confidence: 99%

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

Aizawa¹

2014

J Antivir Antiretrovir

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A first-generation protease inhibitor (PI) against HCV non-structural 3/4A serine protease was approved worldwide at the end of 2011. We are now facing a revolutionary change in therapeutic strategies for chronic HCV infection, from interferon (IFN)-based therapies to direct-acting antivirals (DAAs). The efficacy of antiviral therapy varies with HCV genotype. The most intractable and most common HCV worldwide is HCV genotype 1 (G1). Viral and host factors participating in the virological outcome of IFN-based therapy have been extensively examined. However, in the era of DAAs, the significance of these factors will gradually decrease. Instead, viral factors related to resistance against DAAs are becoming the main focus. In this review, the viral factors participating in the response to IFN-based therapies are summarized, and the issue of viral resistance to DAAs is discussed.

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Sequence Heterogeneity in NS5A of Hepatitis C Virus Genotypes 2a and 2b and Clinical Outcome of Pegylated-Interferon/Ribavirin Therapy

Cited by 16 publications

References 36 publications

Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C

Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C

NS5A Sequence Heterogeneity of Hepatitis C Virus Genotype 4a Predicts Clinical Outcome of Pegylated-Interferon–Ribavirin Therapy in Egyptian Patients

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

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