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Abdelsalam MM, El-Mahdy N, Abou-Saif S. Direct-acting antivirals sofosbuvir and daclatasvir attenuate carbon tetrachloride-induced liver fibrosis in mice. LIVER RESEARCH 2023; 7:71-81. [PMID: 39959700 PMCID: PMC11791913 DOI: 10.1016/j.livres.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/14/2022] [Accepted: 02/02/2023] [Indexed: 03/16/2023]
Abstract
Background and aim Advanced liver fibrosis is a major risk for developing hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) patients. Direct-acting antivirals (DAAs) which are used for treating HCV infection, produce more than 90% cure rate but do not seem to diminish the rate of occurrence or recurrence of HCC. This study aimed to investigate the effect of DAAs sofosbuvir (SOF) and daclatasvir (DAC) on carbon tetrachloride (CCl4)-induced fibrotic changes in mice. Methods Eighty adult male Swiss albino mice were randomly allocated into 8 groups (10 mice/group): normal control group, SOF group (receiving SOF 80 mg/kg body weight (BW), oral gavage, daily), DAC group (receiving DAC 30 mg/kg BW, oral gavage, daily), SOF + DAC group (receiving a combination of both, daily), CCl4 model group (receiving CCl4 2 mL/kg BW, intraperitoneal twice weekly) and three CCl4-intoxicated groups receiving either SOF or DAC or their combination. All CCl4 groups received CCl4 for 12 weeks followed by DAAs for another 12 weeks. Results CCl4-induced a significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and produced histopathological evidence of fibrosis and liver degeneration along with a significant increase (P ≤ 0.001) of the proliferation markers (proliferating cell nuclear antigen (PCNA) and Ki-67), hepatic stellate cells (HSCs) activation markers (alpha-smooth muscle actin (α-SMA) and glial fibrillary acidic protein (GFAP)), fibrosis marker (matrix metalloproteinase-9 (MMP-9)) and pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α)). CCl4-intoxicated mice treated with SOF, DAC, or their combination revealed a significant amelioration (P ≤ 0.001) of CCl4-induced elevation of liver enzymes, fibrotic changes, and liver degeneration along with a significant attenuation (P ≤ 0.001) of CCl4-induced upregulation of all tested markers. The effects of SOF, DAC, and their combination on liver enzymes were comparable while the effect of SOF + DAC combination on mitigating CCl4-induced upregulation of the proliferation and HSCs activation markers was significantly stronger than either SOF or DAC alone. As for MMP-9 and TNF-α, the effects of DAC and SOF + DAC combination were comparable and both were more significant than that of SOF alone. Conclusions SOF and DAC may possess an antifibrotic effect that is independent of their role as antiviral agents against CCl4-induced liver injury. This might exclude the role of DAAs in early occurrence or accelerated recurrence of HCC through the progression of the HCV patients' pre-existing fibrosis. However, HCC patients treated with DAAs should be closely monitored with continuous HCC surveillance during and post-therapy.
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Affiliation(s)
- Mayadah M. Abdelsalam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Nageh El-Mahdy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Sabry Abou-Saif
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
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Zakaria S, El-Sisi AE. Daclatasvir and Sofosbuvir Mitigate Hepatic Fibrosis Through Downregulation of TNF-α / NF-κB Signaling Pathway. Curr Mol Pharmacol 2021; 13:318-327. [PMID: 31951178 DOI: 10.2174/1874467213666200116114919] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/02/2019] [Accepted: 12/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic fibrosis is the major issue in chronic liver diseases such as chronic hepatitis C virus (HCV). The newly approved direct acting antiviral (DAA) agents such as Sofosbuvir (SOF) and daclatasvir (DAC) have been found to be associated with decreased fibrotic markers in HCV patients. AIM This study tried to explore whether the reported antifibrotic effect of these drugs is antiviral dependent or drug induced. METHOD Hepatic fibrosis was induced by (0.5ml/kg) CCl4 IP twice a week for six weeks. SOF (20 mg/kg/d) and DAC (30 mg/kg/d) were added in the last four weeks of treatments. Liver functions, fibrotic markers such as Hyaluronic acid and metalloproteinase-9 were detected using immunoassay. The expression of TNF-α/NF-κB signaling pathway as well as Bcl-2 were done using immunoassay. RESULTS SOF and DAC exerted a potent antifibrotic effect evidenced by their activity against hyaluronic acid HA and metalloproteinase MMP-9 significantly (P≤0.001). This effect was further proved histopathologically where liver tissues from rats treated by drugs showed marked inhibition of collagen precipitation as well as inhibition of HSCs activation. This antifibrotic action was associated with decreased expression of TNF-α /NF-κB signaling pathway and induction of Bcl-2. CONCLUSION SOF/ DAC antifibrotic effect is independent of its antiviral activity. The molecular events associated with this effect were the downregulation of TNF-α / NF-κB signaling pathway and induction of Bcl-2.
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Affiliation(s)
- Sherin Zakaria
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, Kaferelsheikh, Egypt
| | - Alaa E El-Sisi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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Yoneyama H, Morishita A, Iwama H, Fujita K, Masaki T, Tani J, Tadokoro T, Nomura T, Sakamoto T, Oura K, Takuma K, Nakahara M, Mimura S, Deguchi A, Oryu M, Tsutsui K, Himoto T, Shimotohno K, Wakita T, Kobara H, Masaki T. Identification of microRNA associated with the elimination of hepatitis C virus genotype 1b by direct-acting antiviral therapies. J Gastroenterol Hepatol 2021; 36:1126-1135. [PMID: 32839985 DOI: 10.1111/jgh.15224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Direct-acting antiviral (DAA) therapies have been proven to be highly effective for the eradication of hepatitis C virus (HCV) without resistance-associated substitutions (RASs). However, even in cases with no detected RASs, treatment sometimes fails, suggestive of the existence of some host-related factors involved in HCV eradication by DAAs. To explore such factors, we analyzed the serum microRNAs (miRNAs) of patients who received DAA treatment. METHODS The serum miRNA expression levels of 39 patients with chronic HCV infection without any detectable RASs, who achieved sustained virological response with asunaprevir/daclatasvir or grazoprevir/elbasvir therapy, were investigated cyclopedically, using oligonucleotide microarrays. The effects of specific miRNAs on the replication of HCV were measured in the HCV genomic replicon containing Huh-7 hepatoma cells. RESULTS Along with the disappearance of HCV, the expression quantiles of 16 miRNAs in the asunaprevir/daclatasvir group and 18 miRNAs in the grazoprevir/elbasvir group showed a tendency to increase or decrease. Among these molecules, adjustments for multiple testing yielded a significant differential expression at a false discovery rate of less than 5% for only one molecule, hsa-miR-762. Its expression quantile increased after HCV exclusion in all patients who had achieved sustained virological response. Quantitative polymerase chain reaction analysis validated a significant increase in the serum hsa-miR-762 after disappearance of HCV. On the contrary, hsa-miR-762 was decreased in the relapse and breakthrough of HCV in DAA failures. Transfection of hsa-miR-762 into cultured HCV-infected hepatocytes significantly decreased HCV-RNA replication. CONCLUSION These data suggest that hsa-miR-762 is one of the host factors participating in HCV exclusion by DAA therapy.
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Affiliation(s)
- Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Miki, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takahiro Masaki
- Department of Laboratory Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Makoto Oryu
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Kunihiko Tsutsui
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa, Japan
| | - Kunitada Shimotohno
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Toyama, Tokyo, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
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Zhang LL, Li JL, Ji MX, Tian D, Wang LY, Chen C, Tian M. Attenuated P. falciparum Parasite Shows Cytokine Variations in Humanized Mice. Front Immunol 2020; 11:1801. [PMID: 33013831 PMCID: PMC7516016 DOI: 10.3389/fimmu.2020.01801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/06/2020] [Indexed: 12/17/2022] Open
Abstract
A recently developed humanized mouse has been used to assess the immune response evoked against the isolated attenuated C9 parasite clone (C9-M; carrying a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500) of Plasmodium falciparum. Significant human RBC engraftment was achieved by ameliorating the residual non-adaptive immune response using clodronate-loaded liposome treatment. Controlled reactive professional phagocytic leukocytes in immunodeficient mice allowed for sizeable human blood chimerism and injected huRBCs acted as bona fide host cells for P. falciparum. huRBC-reconstituted immunodeficient mice received infectious challenge with attenuated P. falciparum C9 parasite mutants (C9-M), complemented (C9-C), and wild type (NF54) progenitors to study the role of immune effectors in the clearance of the parasite from mouse circulation. C9-M and NF54 parasites grew and developed in the huRBC-reconstituted humanized NSG mice. Further, the presence of mutant parasites in deep-seated tissues suggests the escape of parasites from the host's immune responses and thus extended the survival of the parasite. Our results suggest an evasion mechanism that may have been employed by the parasite to survive the mouse's residual non-adaptive immune responses. Collectively, our data suggest that huRBCs reconstituted NSG mice infected with attenuated P. falciparum is a valuable tool to explore the role of C9 mutation in the growth and survival of parasite mutants and their response to the host's immune responses. This mouse might help in identifying novel chemotherapeutic targets to develop new anti-malarial drugs.
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Affiliation(s)
- Lei-Lei Zhang
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Jin-Long Li
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ming-Xin Ji
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Dan Tian
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Li-Yan Wang
- Department of Operating Room, The Second Hospital of Jilin University, Changchun, China
| | - Chen Chen
- Department of Operating Room, The Second Hospital of Jilin University, Changchun, China
| | - Miao Tian
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, China
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Hepatitis C virus enhances Rubicon expression, leading to autophagy inhibition and intracellular innate immune activation. Sci Rep 2020; 10:15290. [PMID: 32943718 PMCID: PMC7498609 DOI: 10.1038/s41598-020-72294-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/18/2020] [Indexed: 12/19/2022] Open
Abstract
Autophagy, a degradation system, works to maintain cellular homeostasis. However, as the impact of Hepatitis C virus (HCV) infection on hepatocyte autophagy and its effect on HCV replication remain unclear, we examined them. HCV infection suppressed late-stage autophagy and increased Rubicon. siRNA-mediated knockdown of Rubicon promoted autophagy in HCV-infected cells. In Huh-7 cells harbouring the HCV replicon, Rubicon knockdown downregulated the expression of type 1 interferon (IFN)-related genes and upregulated HCV replication. Rubicon overexpression or administration of bafilomycin A1 or chloroquine, an inhibitor of late-stage autophagy, suppressed autophagy and activated the type 1 IFN pathway. On the other hand, Atg7 knockout suppressed early-stage autophagy and did not activate the type 1 IFN pathway. In livers of humanized liver chimeric mice, HCV infection increased Rubicon and enhanced type 1 IFN signalling. Elimination of HCV in the mice reduced the increase in Rubicon due to HCV infection. The expression levels of Rubicon and IFN-stimulated genes in chronic hepatitis C patients were higher than those in non-B, non-C hepatitis patients. HCV infection increased Rubicon and suppressed hepatocyte autophagy, leading to activation of the intracellular immune response. Rubicon induction is involved in HCV replication via activation of the intracellular immune response.
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Pre-existing minor variants with NS5A L31M/V-Y93H double substitution are closely linked to virologic failure with asunaprevir plus daclatasvir treatment for genotype 1b hepatitis C virus infection. PLoS One 2020; 15:e0234811. [PMID: 32544182 PMCID: PMC7297368 DOI: 10.1371/journal.pone.0234811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 06/02/2020] [Indexed: 12/15/2022] Open
Abstract
Background L31 and Y93 in the NS5A region of the hepatitis C virus (HCV) are the most important substitution positions associated with resistance to direct-acting antiviral (DAA) treatment. Methods We analyzed the frequency of NS5A L31M/V and Y93/H in NS5A inhibitor-naive HCV genotype 1 patients who received asunaprevir plus daclatasvir combination treatment using a conventional sequencing method and a deep sequencing method that can distinguish a single substitution at either position and a double substitution at both positions with a 0.1% detection threshold. Results The frequency of substitutions at both sites using the conventional method was very low, with 1 in 14 non-responders and 0 in 42 randomly selected responder patients. On the other hand, for the deep sequencing method, cases with double substitutions in the tandem sequence were detected in 8/14 non-responders and 1/42 responders (p<0.0001). For the conventional method, substitutions were detected at any position in 6/14 non-responders and 2/42 responders (p = 0.0019), with a clear difference between the two groups. The difference was also clear with the deep sequencing method, with 11/14 non-responders and 8/42 responders. Interestingly, for the deep sequencing method, the single substitution of L31 was found in 6/14 non-responders and 7/42 responders, whereas single substitutions of Y93 or double substitutions were found in 7/14 vs. 1/42 and 8/14 vs. 1/42 patients, respectively. Conclusions NS5A L31 and Y93 substitutions were detected in tandem by the deep sequencing methods in several genotype 1 patients, who may be more resistant to DAA treatment containing an NS5A inhibitor.
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Takeda H, Yamashita T, Ueda Y, Sekine A. Exploring the hepatitis C virus genome using single molecule real-time sequencing. World J Gastroenterol 2019; 25:4661-4672. [PMID: 31528092 PMCID: PMC6718035 DOI: 10.3748/wjg.v25.i32.4661] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Single molecular real-time (SMRT) sequencing, also called third-generation sequencing, is a novel sequencing technique capable of generating extremely long contiguous sequence reads. While conventional short-read sequencing cannot evaluate the linkage of nucleotide substitutions distant from one another, SMRT sequencing can directly demonstrate linkage of nucleotide changes over a span of more than 20 kbp, and thus can be applied to directly examine the haplotypes of viruses or bacteria whose genome structures are changing in real time. In addition, an error correction method (circular consensus sequencing) has been established and repeated sequencing of a single-molecule DNA template can result in extremely high accuracy. The advantages of long read sequencing enable accurate determination of the haplotypes of individual viral clones. SMRT sequencing has been applied in various studies of viral genomes including determination of the full-length contiguous genome sequence of hepatitis C virus (HCV), targeted deep sequencing of the HCV NS5A gene, and assessment of heterogeneity among viral populations. Recently, the emergence of multi-drug resistant HCV viruses has become a significant clinical issue and has been also demonstrated using SMRT sequencing. In this review, we introduce the novel third-generation PacBio RSII/Sequel systems, compare them with conventional next-generation sequencers, and summarize previous studies in which SMRT sequencing technology has been applied for HCV genome analysis. We also refer to another long-read sequencing platform, nanopore sequencing technology, and discuss the advantages, limitations and future perspectives in using these third-generation sequencers for HCV genome analysis.
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Affiliation(s)
- Haruhiko Takeda
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Taiki Yamashita
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Akihiro Sekine
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
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Doi A, Hikita H, Kai Y, Tahata Y, Saito Y, Nakabori T, Yamada R, Kodama T, Sakamori R, Murayama A, Nitta S, Asahina Y, Suemizu H, Tatsumi T, Kato T, Takehara T. Combinations of two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents are effective for hepatitis C virus with NS5A-P32 deletion in humanized-liver mice. J Gastroenterol 2019; 54:449-458. [PMID: 30684016 DOI: 10.1007/s00535-018-01541-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 12/19/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND The emergence of a deletion mutant at hepatitis C virus (HCV) NS5A-P32 (P32del) has recently been reported in a subset of chronic hepatitis C patients who experience virologic failure after direct-acting antiviral drug (DAA) treatment. This mutation confers extremely high resistance to NS5A inhibitors. No effective treatment has been established for cases with this mutation. METHODS We used a JFH1-based recombinant virus with NS5A from a genotype 1b strain to introduce a P32del mutation. We inoculated human hepatocyte chimeric mice with sera from a patient with ledipasvir/sofosbuvir therapy failure carrying a genotype 1b HCV with NS5A L31M and P32del or from a DAA-naïve patient carrying wild-type virus. RESULTS JFH1-based chimeric viruses with P32del showed sufficient levels of replication for in vitro assay despite the suppression of viral growth and infectious virus production. Variants with P32del exhibited severe resistance to all tested NS5A inhibitors, including daclatasvir, ledipasvir, elbasvir and velpatasvir, but were as susceptible to NS3/4A inhibitors, NS5B inhibitors, interferon alfa-2b, and ribavirin as wild-type viruses in the in vitro assay. The P32del mutant virus caused persistent infection in all inoculated chimeric mice with high viral titer and frequency. The virus was resistant to the ledipasvir/GS-558093 (a nucleotide analog inhibitor of NS5B polymerase) regimen but susceptible to either simeprevir plus GS-558093 or peg-interferon alfa-2b, compared to the wild-type virus. CONCLUSION Therapies combining at least two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents may be effective for HCV-infected patients with NS5A-P32del.
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Affiliation(s)
- Akira Doi
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hayato Hikita
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yugo Kai
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Tahata
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshinobu Saito
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tasuku Nakabori
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryoko Yamada
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Kodama
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryotaro Sakamori
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 4-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 4-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, 4-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hiroshi Suemizu
- Department of Laboratory Animal Research, Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
| | - Tomohide Tatsumi
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Tetsuo Takehara
- Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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El-Sisi AE, Zakaria S. Potential Anti-Fibrotic Effect of Direct Acting Antiviral Drugs on CCl4 Induced Hepatic Fibrosis in Rats. EGYPTIAN JOURNAL OF BASIC AND CLINICAL PHARMACOLOGY 2019. [DOI: 10.32527/2019/101414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Alaa E. El-Sisi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Sherin Zakaria
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, Kaferelsheikh, Egypt
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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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11
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Ishigami M, Hayashi K, Honda T, Kuzuya T, Ishizu Y, Ishikawa T, Nakano I, Urano F, Kumada T, Yoshioka K, Hirooka Y, Goto H. Daclatasvir and asunaprevir treatment in patients infected by genotype 1b of hepatitis C virus with no or subtle resistant associated substitutions (RAS) in NS5A-Y93. J Med Virol 2018; 90:736-744. [PMID: 29111616 DOI: 10.1002/jmv.24978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 10/12/2017] [Indexed: 02/07/2023]
Abstract
In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan, daclatasvir and asunaprevir (DCV+ASV), in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). Among 924 patients registered in our multicenter study, 750 patients who were proven not to be infected with NS5A-Y93H RAS by direct sequencing and to have no or subtle amount (less than 20%) of NS5A-Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti-viral effect and factors associated with SVR12. In statistical analysis, P < 0.05 was considered as significant. The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were male (odds ratio: 2.128; 95%CI: 1.134-4.000, P = 0.019); lower serum γGTP (odds ratio: 1.007; 95%CI: 1.002-1.012, P = 0.006); lower HCV-RNA (odds ratio: 1.848; 95%CI: 1.087-3.145, P = 0.023), and RVR (odds ratio: 6.250; 95%CI: 2.445-15.873, P < 0.001). No patients with γGTP ≧ 80 IU/L without RVR showed SVR12 (0/4, 0%) and one patients with γGTP ≧ 20-< 80 IU/L and HCV-RNA ≧ 6.5 logIU/mL without RVR (5/10, 50%) and two female patients with RVR but γGTP ≧ 80 IU/L and HCV-RNA ≧ 6.5 logIU/mL (7/13, 53.8%) showed a low SVR12 rate. In the present study, we showed a good viral response with DCV-ASV treatment and identified four predictive factors associated with SVR12. These four markers could be a good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A-Y93.
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Affiliation(s)
- Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Isao Nakano
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Fumihiro Urano
- Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Kentaro Yoshioka
- Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University, Toyoake, Aichi, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
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12
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Iio E, Shimada N, Takaguchi K, Senoh T, Eguchi Y, Atsukawa M, Tsubota A, Abe H, Kato K, Kusakabe A, Miyaki T, Matsuura K, Matsunami K, Shinkai N, Fujiwara K, Nojiri S, Tanaka Y. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res 2017; 47:1308-1316. [PMID: 28332272 DOI: 10.1111/hepr.12898] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/02/2017] [Accepted: 03/20/2017] [Indexed: 12/17/2022]
Abstract
AIM This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy. METHODS Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing. RESULTS Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P < 0.001). Among 26 patients with prior DCV/ASV therapy, the prevalence of NS5A multi-RAVs (≥2) was similar between responders and non-responders (61% [11/18] vs. 75% [5/8]), but all patients without RAVs achieved SVR. Multivariate analysis showed that prior DCV/ASV therapy and history of hepatocellular carcinoma were independently associated with treatment failure (odds ratio, 37.55; 95% confidence interval, 10.78-130.76; P < 0.001 for prior DCV/ASV therapy; odds ratio, 4.42; 95% confidence interval, 1.09-18.04; P = 0.03 for the history of HCC). All SOF/LDV failure patients (n = 8) with prior DCV/ASV treatment had two or more factors of cirrhosis, IL28B unfavorable genotype, and baseline NS5A multi-RAVs. The multiple NS5A RAVs had increased but NS5B substitutions, C316N/A207T/A218S or L159F, had not changed at the time of relapse. CONCLUSIONS Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.
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Affiliation(s)
- Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | | | | | | | | | | | | | - Hiroshi Abe
- Jikei University School of Medicine, Katsushika Medical Center, Tokyo, Japan
| | - Keizo Kato
- Jikei University School of Medicine, Tokyo, Japan
- Shinmatsudo Central General Hospital, Matsudo, Japan
| | | | | | - Kentaro Matsuura
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kayoko Matsunami
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Noboru Shinkai
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kei Fujiwara
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shunsuke Nojiri
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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13
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Ikegami T, Ueda Y, Akamatsu N, Ishiyama K, Goto R, Soyama A, Kuramitsu K, Honda M, Shinoda M, Yoshizumi T, Okajima H, Kitagawa Y, Inomata Y, Ku Y, Eguchi S, Taketomi A, Ohdan H, Kokudo N, Shimada M, Yanaga K, Furukawa H, Uemoto S, Maehara Y. Asunaprevir and daclatasvir for recurrent hepatitis C after liver transplantation: A Japanese multicenter experience. Clin Transplant 2017; 31. [PMID: 28881052 DOI: 10.1111/ctr.13109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2017] [Indexed: 02/06/2023]
Abstract
The safety and efficacy of an IFN-free regimen using asunaprevir (ASV) and daclatasvir (DCV) for recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) have not been evaluated in Japan. A multicenter study of LT recipients (n = 74) with recurrent HCV genotype 1b infection treated with ASV-DCV for 24 weeks was performed. Medical history was positive for pegylated interferon and ribavirin (Peg-IFN/RBV) in 40 (54.1%) patients, and for simeprevir (SMV) with Peg-IFN/RBV in 12 (16.2%) patients. Resistance-associated variants (RAVs) were positive at D168 (n = 1) in the NS3, and at L31 (n = 4), Y93 (n = 4), and L31/Y93 (n = 1) in the NS5A region of the HCV genome. Sixty-one (82.4%) patients completed the 24-week treatment protocol. Although sustained viral response (SVR) was achieved in 49 (80.3%) patients, it was achieved in only two (16.7%) patients among those with histories of receiving SMV (n = 12). Univariate analysis showed that a history of SMV (P < .01) and the presence of mutations in NS5A (P = .02) were the significant factors for no-SVR. By excluding the patients with either a history of SMV-based treatment or RAVs in NS3/NS5A, the SVR rate was 96.4%. By excluding the patients with a history of SMV and those with RAVs in NS3/NS5A, viral clearance of ASV-DCV was favorable, with a high SVR rate.
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Affiliation(s)
- Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuhisa Akamatsu
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Kohei Ishiyama
- Department of Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kaori Kuramitsu
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masaki Honda
- Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideaki Okajima
- Department of Surgery, University of Tokushima, Tokushima, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yukihiro Inomata
- Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yonson Ku
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Hideki Ohdan
- Department of Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Norihiro Kokudo
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Mitsuo Shimada
- Department of Surgery, University of Tokushima, Tokushima, Japan
| | - Katsuhiko Yanaga
- Department of Surgery, School of Medicine, The Jikei University, Tokyo, Japan
| | - Hiroyuki Furukawa
- Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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14
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Suda G, Ogawa K, Yamamoto Y, Katagiri M, Furuya K, Kumagai K, Konno J, Kimura M, Kawagishi N, Ohara M, Umemura M, Ito J, Izumi T, Nakai M, Sho T, Natsuizaka M, Morikawa K, Tsubota A, Shimada N, Iio E, Tanaka Y, Sakamoto N. Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy. J Gastroenterol 2017; 52:1122-1129. [PMID: 28315983 DOI: 10.1007/s00535-017-1328-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 03/02/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy. METHODS This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12 weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated. RESULTS Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7% (13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92 K at baseline. CONCLUSIONS This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | | | | | - Ken Furuya
- JCHO Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Kenichi Kumagai
- Mori City National Health Insurance Hospital, Mori, Hokkaido, Japan
| | - Jun Konno
- Hakodate Central General Hospital, Hakodate, Hokkaido, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Division of Molecular Cell Biology, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Chiba, Japan
| | - Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
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15
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Morishita N, Hiramatsu N, Oze T, Urabe A, Tahata Y, Yamada R, Yakushijin T, Hosui A, Iio S, Yamada A, Hagiwara H, Mita E, Yamada Y, Ito T, Inada M, Katayama K, Yabuuchi I, Imai Y, Hikita H, Sakamori R, Yoshida Y, Tatsumi T, Hayashi N, Takehara T. Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection. Hepatol Res 2017; 47:773-782. [PMID: 27593967 DOI: 10.1111/hepr.12817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 07/15/2016] [Accepted: 08/31/2016] [Indexed: 01/13/2023]
Abstract
AIM Simeprevir (SMV)-based triple therapy is an effective retreatment option following failure of telaprevir (TVR)-based triple therapy. However, it is unclear whether the persistence of resistance-associated variants (RAVs) induced by TVR-based therapy may reduce the treatment effect of SMV-based therapy. METHODS The factors associated with the treatment effect, including RAVs in the NS3 region, were examined in 21 patients with genotype 1b HCV infection who were treated with SMV-based therapy after failure of TVR-based therapy. Ultra-deep sequencing was carried out to detect RAVs. RESULTS With the exception of one patient who discontinued treatment owing to adverse events, the sustained virologic response (SVR) rate was 50% (10/20). Ultra-deep sequencing at the start of SMV-based therapy revealed that TVR-resistant variants were detected in six patients (29%), and no variants were observed at position 168. Cross-resistance between TVR and SMV with low frequency was detected in only one patient, and this patient achieved SVR. Higher SVRs for SMV-based therapy were attained in patients who discontinued treatment owing to the adverse effects of prior TVR-based therapy (discontinuation 100% vs. non-discontinuation 29%, P = 0.005), and patients who relapsed following prior pegylated interferon plus ribavirin therapy (relapse 100% vs. non-response 20%, P = 0.007). CONCLUSIONS In this study, ultra-deep sequencing analysis revealed that TVR and/or SMV-resistant variants may have no influence on the effect of SMV-based therapy after failure of TVR-based therapy. Patients who discontinued treatment owing to adverse effects of TVR-based therapy and relapsers to previous pegylated interferon/ribavirin therapy would be good candidates for retreatment with SMV-based therapy.
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Affiliation(s)
- Naoki Morishita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Sadaharu Iio
- Higashiosaka City General Hospital, Higashiosaka, Japan
| | | | | | - Eiji Mita
- National Hospital Organization Osaka National Hospital, Osaka, Japan
| | | | - Toshifumi Ito
- Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | | | - Kazuhiro Katayama
- Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Iwao Yabuuchi
- National Hospital Organization Minami Wakayama Medical Center, Tanabe, Japan
| | | | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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16
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Baseline quasispecies selection and novel mutations contribute to emerging resistance-associated substitutions in hepatitis C virus after direct-acting antiviral treatment. Sci Rep 2017; 7:41660. [PMID: 28134353 PMCID: PMC5278351 DOI: 10.1038/srep41660] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 12/12/2016] [Indexed: 12/11/2022] Open
Abstract
Resistance-associated substitutions (RASs) in hepatitis C virus (HCV) appear upon failure of treatment with direct-acting antivirals (DAAs). However, their origin has not been clarified in detail. Among 11 HCV genotype 1b patients who experienced virologic failure with asunaprevir (ASV)/daclatasvir (DCV), 10 had major NS5A L31M/V-Y93H variants after treatment. L31M/V-Y93H variants were detected as a minor clone before therapy in 6 patients and were the most closely related to the post-treatment variants by phylogenetic tree analysis in 4 patients. Next, to consider the involvement of a trace amount of pre-existing variants below the detection limit, we analysed human hepatocyte chimeric mice infected with DAA-naïve patient serum. L31V-Y93H variants emerged after treatment with ledipasvir (LDV)/GS-558093 (nucleotide NS5B inhibitor) and decreased under the detection limit, but these variants were dissimilar to the L31V-Y93H variants reappearing after ASV/DCV re-treatment. Finally, to develop an infection derived from a single HCV clone, we intrahepatically injected full-genome HCV RNA (engineered based on the wild-type genotype 1b sequence) into chimeric mice. A new Y93H mutation actually occurred in this model after LDV monotherapy failure. In conclusion, post-treatment RASs appear by 2 mechanisms: the selection of pre-existing substitutions among quasispecies and the generation of novel mutations during therapy.
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Wang HL, Lu X, Yang X, Xu N. Effectiveness and safety of daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: Systematic review and meta-analysis. J Gastroenterol Hepatol 2017; 32:45-52. [PMID: 27597318 DOI: 10.1111/jgh.13587] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/29/2016] [Accepted: 08/24/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b infection. A definite conclusion about efficacy and safety of DCV + ASV in patients with HCV genotype 1b is not available. A meta-analysis was conducted to evaluate outcomes of all-oral treatment with DCV + ASV in terms of sustained virological response at 12 (SVR12 ) and 24 (SVR24 ) weeks and adverse effects after the end of treatment. METHODS PUBMED, MEDLINE, and EMBASE databases were searched in May 2016. The data were analyzed with Review Manager 5.3. RESULTS Nine trials (n = 1690) met entry criteria. SVR12 was achieved by 89.9% of treatment-naïve patients, 84.7% of interferon-ineligible/intolerant patients, and 81.9% of nonresponder patients. Moreover, 89.0% of interferon-ineligible/intolerant patients and 83.1% of nonresponder patients achieved SVR24 . Baseline characteristics, including gender, race, advanced age, non-CC IL28B genotype, and cirrhosis, did not appear to impact SVR rates. However, the rate of SVR12 in all patients with viral load < 8 × 105 was higher than that of all those with viral load ≥ 8 × 105 (151/162 vs 625/753). Moreover, pre-existing nonstructural protein 5A resistance-associated variants (RAVs) were associated with virological failure during DCV + ASV therapy, resulting in the emergence of multiple RAVs. Treatment with DCV + ASV was well tolerated, with low incidences of serious adverse effects, discontinuations, and grade 3 or 4 laboratory abnormalities in all patients. CONCLUSIONS Daclatasvir plus asunaprevir provides a highly effective and well-tolerated treatment option for patients with HCV genotype 1b. However, patients with nonstructural protein 5A RAVs at baseline should be assessed to optimize more potent direct antiviral agent therapies.
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Affiliation(s)
- Hui-Lian Wang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Xi Lu
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Xudong Yang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Nan Xu
- 2nd Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China
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Iio E, Shimada N, Abe H, Atsukawa M, Yoshizawa K, Takaguchi K, Eguchi Y, Nomura H, Kuramitsu T, Kang JH, Matsui T, Hirashima N, Tsubota A, Kusakabe A, Hasegawa I, Miyaki T, Shinkai N, Fujiwara K, Nojiri S, Tanaka Y. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol 2017; 52:94-103. [PMID: 27236547 DOI: 10.1007/s00535-016-1225-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 05/11/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.
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Affiliation(s)
- Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | | | - Hiroshi Abe
- Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan
| | | | | | | | | | | | | | | | | | - Noboru Hirashima
- National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | | | | | - Izumi Hasegawa
- Japan Community Health Care Organization, Chukyo Hospital, Nagoya, Japan
| | | | - Noboru Shinkai
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | - Kei Fujiwara
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | - Shunsuke Nojiri
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan.
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Ito J, Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kumagai K, Kikuchi H, Miyagishima T, Kobayashi T, Kimura M, Yamasaki K, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Terashita K, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection. Hepatol Res 2016; 46:1294-1303. [PMID: 26896756 DOI: 10.1111/hepr.12685] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 01/27/2016] [Accepted: 02/15/2016] [Indexed: 02/08/2023]
Abstract
AIM Sofosbuvir (SOF), a nucleotide analog pro-drug, targets hepatitis C virus (HCV) NS5B polymerase and shows potential for treating HCV infection, given its high efficacy and good barrier to resistance. However, in addition to the rare resistant-associated variant (RAV) of non-structural protein NS5B S282T, several new potential RAVs of SOF have been reported, especially related to HCV genotype 1b. However, the prevalence and characteristics of these RAVs have not been clarified. METHODS We analyzed the prevalence of variants in the NS3/NS5A/NS5B regions in 96 patients treated with simeprevir (SMV) combination therapy, and the prevalence of RAVs in patients showing treatment failure was determined by direct- or deep-sequencing methods. Associations between these potential RAVs and clinical factors were also analyzed. RESULTS Prevalence of NS5B RAV C316N was high (46.9%, 45/96), whereas that of NS5B L159F was relatively low (1.04%, 1/96); however, deep sequencing showed that 30.0% of patients with C316N also had NS5B RAV L159F. Additionally, there was no significant relationship between the existence of potential NS5B and NS5A or NS3 RAVs. However, the presence of NS5B C316N was significantly associated with an HCV core amino acid 91 substitution. No significant difference was detected between each RAV and sustained virological response in simeprevir combination therapy. CONCLUSION We provide clear evidence of the high prevalence of two potential naturally occurring NS5B RAVs (C316N and L159F) in Japan. It may be important to pay particular attention to these new potential RAVs, especially when using SOF-based therapy in patients with RAVs due to previous direct-acting antiviral therapy failure.
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Affiliation(s)
- Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Yoshiya Yamamoto
- Department of Gastroenterology, Hakodate City General Hospital, Hakodate
| | - Atsushi Nagasaka
- Department of Gastroenterology, Sapporo City General Hospital, Sapporo
| | - Ken Furuya
- Department of Gastroenterology, JCHO Hokkaido Hospital, Sapporo
| | - Kenichi Kumagai
- Department of Gastroenterology, Hakodate Medical Association Hospital, Hakodate
| | - Hideaki Kikuchi
- Department of Gastroenterology, Obihiro-Kosei General Hospital, Obihiro
| | - Takuto Miyagishima
- Department of Internal Medicine and Gastroenterology, Kushiro Rosai Hospital, Kushiro
| | - Tomoe Kobayashi
- Department of Gastroenterology, Tomakomai City Hospital, Tomakomai, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Kazushi Yamasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Seiji Tsunematsu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Fumiyuki Sato
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Yoko Tsukuda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo
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Uchida Y, Kouyama JI, Naiki K, Sugawara K, Inao M, Imai Y, Nakayama N, Mochida S. Development of rare resistance-associated variants that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy by a two-hit mechanism. Hepatol Res 2016; 46:1234-1246. [PMID: 26878268 DOI: 10.1111/hepr.12673] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 02/09/2016] [Accepted: 02/10/2016] [Indexed: 12/25/2022]
Abstract
AIM The virologic characteristics of resistance-associated variants (RAVs) developing in patients receiving dual oral therapy with daclatasvir/asunaprevir, including those with previous triple therapy with simeprevir, were evaluated. METHODS A total of 206 patients with genotype-1b HCV infection, including 5 patients with previous simeprevir therapy, were treated with daclatasvir/asunaprevir for 24 weeks. Resistance-associated variants in the NS5A regions at baseline and during/after therapy were evaluated using cycling-probe real-time polymerase chain reaction combined with direct sequencing. The dynamics of rare RAVs were also assessed using ultra-deep sequencing. RESULTS A sustained virologic response (SVR12) was achieved in 180 patients (87%); the rates were 95% in patients without baseline NS5A-RAVs and 83%, 59%, and 77% in those with hepatitis C virus (HCV) strains carrying NS5A-L31M, NS5A-Y93H/C, and NS5A-R30Q/H/L mutations, respectively. A multivariate analysis revealed baseline NS5A-R30Q/H/L mutation and NS5A-Y93H mutations as significant factors associated with SVR12. Virologic failure developed in all 5 patients with previous simeprevir treatment, and rare RAVs (HCV strains with NS5A-R30H, NS5A-A92K, NS5A-P29del, and NS5A-P32del) developed at virologic failure. Ultra-deep sequencing revealed that HCV strains with NS5A-P29del or NS5A-P32del were absent at baseline and emerged within 4 weeks of dual oral therapy among the strains appearing after simeprevir administration. CONCLUSION NS5A-R30Q/H/L and NS5A-Y93H mutations at baseline determined the therapeutic efficacy of dual oral therapy with daclatasvir/asunaprevir, but rare NS5A-RAVs developed frequently in patients with previous simeprevir treatment. Such RAVs may develop in a two-hit manner, with simeprevir altering the quasispecies of HCV strains in the NS5A regions, leading to the emergence of HCV strains with NS5A-P29del and NS5A-P32del during exposure to daclatasvir/asunaprevir.
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Affiliation(s)
- Yoshihito Uchida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Jun-Ichi Kouyama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Kayoko Naiki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Kayoko Sugawara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Mie Inao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Yukinori Imai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
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21
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State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization. J Immunol Res 2016; 2016:1412840. [PMID: 27843956 PMCID: PMC5098088 DOI: 10.1155/2016/1412840] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/09/2016] [Accepted: 09/20/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) still represents a major public health threat, with a dramatic burden from both epidemiological and clinical points of view. New generation of direct-acting antiviral agents (DAAs) has been recently introduced in clinical practice promising to cure HCV and to overcome the issues related to the interferon-based therapies. However, the emergence of drug resistance and the suboptimal activity of DAAs therapies against diverse HCV genotypes have been observed, determining treatment failure and hampering an effective control of HCV spread worldwide. Moreover, these treatments remain poorly accessible, particularly in low-income countries. Finally, effective screening strategy is crucial to early identifying and treating all HCV chronically infected patients. For all these reasons, even though new drugs may contribute to impacting HCV spread worldwide a preventive HCV vaccine remains a cornerstone in the road to significantly reduce the HCV spread globally, with the ultimate goal of its eradication. Advances in molecular vaccinology, together with a strong financial, political, and societal support, will enable reaching this fundamental success in the coming years. In this comprehensive review, the state of the art about these major topics in the fight against HCV and the future of research in these fields are discussed.
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Lau G, Benhamou Y, Chen G, Li J, Shao Q, Ji D, Li F, Li B, Liu J, Hou J, Sun J, Wang C, Chen J, Wu V, Wong A, Wong CLP, Tsang STY, Wang Y, Bassit L, Tao S, Jiang Y, Hsiao HM, Ke R, Perelson AS, Schinazi RF. Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study. Lancet Gastroenterol Hepatol 2016; 1:97-104. [PMID: 27917405 PMCID: PMC5131925 DOI: 10.1016/s2468-1253(16)30015-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND To shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue. METHODS In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. FINDINGS Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). No patients experienced any serious adverse events. INTERPRETATION In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings. FUNDING Center for AIDS Research, National Institutes of Health, US Department of Energy, National Center for Research Resources and the Office of Research Infrastructure Programs, Cheng Si-Yuan (China-International) Hepatitis Research Foundation, and Humanity and Health Medical Group.
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Affiliation(s)
| | - Yves Benhamou
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Guofeng Chen
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Jin Li
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Qing Shao
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Dong Ji
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Fan Li
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Bing Li
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Jialiang Liu
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Jinlin Hou
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Jian Sun
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Cheng Wang
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Jing Chen
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Vanessa Wu
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - April Wong
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Chris L P Wong
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Stella T Y Tsang
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Yudong Wang
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Leda Bassit
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Sijia Tao
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Yong Jiang
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Hui-Mien Hsiao
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Ruian Ke
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
| | - Alan S Perelson
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong, Hong Kong SAR, China (Prof G Lau MD, C Wang MD, J Chen PhD, V Wu BSc, A Wong BSc, Y Wang PhD); Second Liver Cirrhosis Diagnosis and Treatment Center (Prof G Lau, Prof G Chen MD, Prof Q Shao MD, D Ji MD, F Li MD, B Li MD, J Liu MD) and Institute of Infectious Disease (Prof J Li MD), 302 Hospital, Beijing, China; Service d’Hépatologie, Hôpital Pitié-Salpêtrière, Paris, France (Y Benhamou MD); State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Prof J Hou MD, Prof J Sun MD, C Wang); Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong SAR, China (C L P Wong PhD, S T Y Tsang PhD); Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA (L Bassit PhD, S Tao PhD, Y Jiang PhD, H-M Hsiao MS, Prof R F Schinazi PhD); Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM, USA (R Ke PhD, A S Perelson PhD); and Department of Mathematics, North Carolina State University, Raleigh, NC, USA (R Ke)
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Coppola N, Minichini C, Starace M, Sagnelli C, Sagnelli E. Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals. J Med Virol 2016; 88:1659-1671. [PMID: 26991255 DOI: 10.1002/jmv.24527] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2016] [Indexed: 12/15/2022]
Abstract
Introduced in 2013-2014, the second- and third-wave directly acting antivirals (DAAs) have strongly enhanced the efficacy and tolerability of anti-HCV treatment, with a sustained virological response (SVR) in 90-95% of cases treated. The majority of patients who did not achieve an SVR were found to be infected with HCV strains with a reduced susceptibility to these drugs. Indeed, the high error rate of the viral polymerase and a fast virion production (100-fold higher than the human immunodeficiency virus) result in a mixture of viral genetic populations (quasi-species) pre-existing treatment initiation. These mutants occur frequently in the NS5A region, with a moderate frequency in the NS3/4A region and rarely in the NS5B region. Treatment-induced resistant mutants to NS5A DAAs persist for years after treatment discontinuation, whereas those resistant to the NS3 DAAs have a shorter duration. This review focuses on the type and prevalence of viral strains with a reduced sensitivity to DAAs, their clinical impact and influence on the response to treatment and, consequently, on treatment choice for DAA-experienced patients. J. Med. Virol. 88:1659-1671, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
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Protease Inhibitor Resistance Remains Even After Mutant Strains Become Undetectable by Deep Sequencing. J Infect Dis 2016; 214:1687-1694. [DOI: 10.1093/infdis/jiw437] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 09/09/2016] [Indexed: 12/13/2022] Open
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Takehara T. [The Catting-edge of Medicine; Anti-viral therapies for chronic hepatitis C]. ACTA ACUST UNITED AC 2016; 105:112-8. [PMID: 27266051 DOI: 10.2169/naika.105.112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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26
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Mouse Systems to Model Hepatitis C Virus Treatment and Associated Resistance. Viruses 2016; 8:v8060176. [PMID: 27338446 PMCID: PMC4926196 DOI: 10.3390/v8060176] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 05/12/2016] [Accepted: 06/16/2016] [Indexed: 12/15/2022] Open
Abstract
While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants.
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