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Del Campo JA, Romero-Gómez M. Modulation of host lipid metabolism by hepatitis C virus: Role of new therapies. World J Gastroenterol 2015; 21:10776-10782. [PMID: 26478669 PMCID: PMC4600579 DOI: 10.3748/wjg.v21.i38.10776] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/07/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
It is well established that hepatitis C virus (HCV) infection and replication relies on host lipid metabolism. HCV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides, circulating infective particles are associated with very low-density lipoprotein. On the other hand, higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HCV infection, suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy (> 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HCV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review, host genetic factors, viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism.
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Aizawa Y, Seki N, Nagano T, Abe H. Chronic hepatitis C virus infection and lipoprotein metabolism. World J Gastroenterol 2015; 21:10299-10313. [PMID: 26420957 PMCID: PMC4579877 DOI: 10.3748/wjg.v21.i36.10299] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 07/11/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is closely associated with the metabolism of lipids and lipoproteins. The main function of lipoproteins is transporting lipids throughout the body. Triglycerides, free cholesterol, cholesteryl esters, and phospholipids are the major components of the transported lipids. The pathway of HCV assembly and secretion is closely linked to lipoprotein production and secretion, and the infectivity of HCV particles largely depends on the interaction of lipoproteins. Moreover, HCV entry into hepatocytes is strongly influenced by lipoproteins. The key lipoprotein molecules mediating these interactions are apolipoproteins. Apolipoproteins are amphipathic proteins on the surface of a lipoprotein particle, which help stabilize lipoprotein structure. They perform a key role in lipoprotein metabolism by serving as receptor ligands, enzyme co-factors, and lipid transport carriers. Understanding the association between the life cycle of HCV and lipoprotein metabolism is important because each step of the life cycle of HCV that is associated with lipoprotein metabolism is a potential target for anti-HCV therapy. In this article, we first concisely review the nature of lipoprotein and its metabolism to better understand the complicated interaction of HCV with lipoprotein. Then, we review the outline of the processes of HCV assembly, secretion, and entry into hepatocytes, focusing on the association with lipoproteins. Finally, we discuss the clinical aspects of disturbed lipid/lipoprotein metabolism and the significance of dyslipoproteinemia in chronic HCV infection with regard to abnormal apolipoproteins.
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Nagano T, Seki N, Tomita Y, Sugita T, Aida Y, Itagaki M, Sutoh S, Abe H, Tsubota A, Aizawa Y. Impact of Chronic Hepatitis C Virus Genotype 1b Infection on Triglyceride Concentration in Serum Lipoprotein Fractions. Int J Mol Sci 2015; 16:20576-94. [PMID: 26334270 PMCID: PMC4613219 DOI: 10.3390/ijms160920576] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/13/2015] [Accepted: 08/20/2015] [Indexed: 12/14/2022] Open
Abstract
Reduced low-density lipoprotein (LDL) cholesterol level is a characteristic feature of dyslipidemia in chronic hepatitis C virus (HCV) infection. However, abnormality in serum triglyceride (TG) has not been fully investigated. To clarify the impact of HCV genotype 1b (G1b) infection and advanced fibrosis on serum TG profiles, TG concentrations in lipoprotein fractions were examined in fasting sera from 185 subjects with active or cleared HCV infection by high-performance liquid chromatography. Serum lipoproteins were fractionated into four classes: chylomicron, very low-density lipoprotein (VLDL), LDL, and high-density lipoprotein (HDL). Then, the significance of HCV G1b infection on TG levels in each lipoprotein fraction was determined using multiple regression models. We found that active HCV G1b infection was positively associated with high HDL-TG levels and low VLDL-TG levels, independent of other factors included in the regression model. In VLDL sub-fractions, active HCV infection was only found to be associated with low levels of large VLDL-TG. Similarly, advanced liver fibrosis in chronic HCV G1b infection was associated with high levels of LDL-TG, HDL-TG, and small VLDL-TG, independent of other clinical factors. These findings indicate that active HCV G1b infection and advanced fibrosis are closely associated with abnormal serum TG profiles.
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Affiliation(s)
- Tomohisa Nagano
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Nobuyoshi Seki
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Yoichi Tomita
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Tomonori Sugita
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Yuta Aida
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Munenori Itagaki
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Satoshi Sutoh
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Hiroshi Abe
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Science, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Yoshio Aizawa
- Department of Gastroenterology and Hepatology Internal Medicine, Jikei University Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan.
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Shimada N, Tsubota A, Atsukawa M, Abe H, Ide T, Takaguchi K, Chuganji Y, Toyoda H, Yoshizawa K, Ika M, Sato Y, Kato K, Kumada T, Sakamoto C, Aizawa Y, Sata M. A 48-week telaprevir-based triple combination therapy improves sustained virological response rate in previous non-responders to peginterferon and ribavirin with genotype 1b chronic hepatitis C: A multicenter study. Hepatol Res 2014; 44:E386-96. [PMID: 24606109 DOI: 10.1111/hepr.12323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/02/2014] [Accepted: 03/05/2014] [Indexed: 02/08/2023]
Abstract
AIM The sustained virological response (SVR) rate of non-responders to peginterferon and ribavirin therapy (PR) is low for 24-week telaprevir-based triple combination therapy (T12PR24), compared to that of treatment-naïve patients or previous-treatment relapsers. This study investigated which characteristics of non-responders were associated with a better SVR rate to 48-week therapy (T12PR48). METHODS A total of 103 Japanese non-responders with genotype 1b chronic hepatitis C received telaprevir-based therapy. Among them, 81 patients (50 partial and 31 null responders) received T12PR24 and 22 (seven partial and 15 null responders) who agreed to the extended therapy received T12PR48. RESULTS Multivariate logistic regression analysis for SVR identified the interleukin-28B (IL28B) rs8099917 TT genotype (P = 0.0005, odds ratio [OR] = 10.38), extended rapid virological response (P = 0.0008, OR = 7.02), T12PR48 regimen (P = 0.0016, OR = 9.31) and previous partial responders (P = 0.0022, OR = 5.89). Among partial responders, the SVR rate did not differ significantly between T12PR48 (85.7%) and T12PR24 (70.0%). Among null responders, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 22.6%, P = 0.0037). Among patients with the IL28B non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (68.8% vs 37.7%, P = 0.0288). Moreover, among null responders with the non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 9.1%, P = 0.0009). CONCLUSION T12PR48 improves the SVR rate in null responders, patients with the non-TT genotype, and null responders with a non-TT genotype.
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Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Japan
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Shimada N, Toyoda H, Tsubota A, Ide T, Takaguchi K, Kato K, Kondoh M, Matsuyama K, Kumada T, Sata M. Baseline factors and very early viral response (week 1) for predicting sustained virological response in telaprevir-based triple combination therapy for Japanese genotype 1b chronic hepatitis C patients: a multicenter study. J Gastroenterol 2014; 49:1485-94. [PMID: 24287582 DOI: 10.1007/s00535-013-0918-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Accepted: 11/11/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients. METHODS A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction. RESULTS Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043). CONCLUSIONS The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥ 4.7 log10 IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.
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Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, 1-380 Shinmatsudo, Matsudo, Chiba, 270-0034, Japan,
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Laird ME, Mohsen A, Duffy D, Mamdouh R, LeFouler L, Casrouge A, El-Daly M, Rafik M, Abdel-Hamid M, Soulier A, Pawlotsky JM, Hézode C, Rosa I, Renard P, Mohamed MK, Bonnard P, Izopet J, Mallet V, Pol S, Albert ML, Fontanet A. Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection. J Hepatol 2014; 61:770-6. [PMID: 24905490 DOI: 10.1016/j.jhep.2014.05.040] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 05/05/2014] [Accepted: 05/25/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment. METHODS We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance. RESULTS Plasma apolipoprotein H (ApoH) levels were significantly higher in patients who achieved spontaneous clearance or responded to pegylated-interferon/ribavirin therapy. Strikingly, patients carrying the IL28B rs12979860 CC SNP correlated with the plasma concentration of ApoH in all three cohorts. Both ApoH and IL28B CC SNP were associated with HCV clearance in univariate analysis. Additional multivariate analysis revealed that the association between IL28B and HCV clearance was closely linked to that of Apo H and HCV clearance, suggesting that both belong to the same biological pathway to clearance. The association between IL28B CC SNP and ApoH was not observed in healthy individuals, suggesting that early post-infection events trigger differential ApoH expression in an IL28B allele dependent manner. CONCLUSIONS This relationship identifies ApoH as the first induced protein quantitative trait associated with IL28B, and characterises a novel host factor implicated in HCV clearance.
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Affiliation(s)
- Melissa E Laird
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France
| | - Amira Mohsen
- Community Medicine Department, National Research Center, Cairo, Egypt
| | - Darragh Duffy
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France
| | - Rasha Mamdouh
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Lenaig LeFouler
- Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France
| | - Armanda Casrouge
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France
| | - Mai El-Daly
- Liver Disease Research Unit, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | - Mona Rafik
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Abdel-Hamid
- Liver Disease Research Unit, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt; Faculty of Medicine, Minia University, Egypt
| | - Alexandre Soulier
- National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France
| | - Christophe Hézode
- INSERM U955, Créteil, France; Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Isabelle Rosa
- INSERM U955, Créteil, France; Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Philippe Renard
- Department of Gastroenterology and Hepatology, Hôpital Victor Dupouy, Argenteuil, France
| | - Mostafa K Mohamed
- Liver Disease Research Unit, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | - Philippe Bonnard
- Maladies Infectieuses et Tropicales, Hôpital Tenon (APHP), Paris, France; INSERM U-707, UPMC, Paris, France
| | - Jacques Izopet
- Department of Virology, CHU Toulouse, Toulouse, France; INSERM U1043, IFR-BMT, Toulouse, France
| | - Vincent Mallet
- Université Paris Descartes, Paris, France; Institut Cochin, INSERM (IMR-S1016), CNRS (UMR 8104), Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hepatologie, Paris, France
| | - Stanislas Pol
- Université Paris Descartes, Paris, France; Institut Cochin, INSERM (IMR-S1016), CNRS (UMR 8104), Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hepatologie, Paris, France
| | - Matthew L Albert
- Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hepatologie, Paris, France.
| | - Arnaud Fontanet
- Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France; Conservatoire National des Arts et Métiers, Paris, France.
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Assessment of the features of serum apolipoprotein profiles in chronic HCV infection: difference between HCV genotypes 1b and 2. Hepatol Int 2014. [PMID: 26202760 DOI: 10.1007/s12072-014-9572-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The life cycle of hepatitis C virus (HCV) is tightly associated with host lipoprotein metabolic pathways. Apolipoprotein is present on the outer surface of lipoprotein particles and plays an important role in lipoprotein metabolism. We aimed to elucidate the influence of chronic HCV infection on serum apolipoprotein profiles. METHODS Fasting serum apolipoprotein profiles of 310 subjects with active or cleared HCV infection were examined. Subsequently, the association between chronic HCV infection and serum apolipoprotein levels was determined using multiple regression analysis. RESULTS Active HCV infection was associated with high serum levels of apo A-II and low serum levels of apo C-II and C-III. HCV infection with both genotype 1b (G1b) and genotype 2 (G2) was associated with low serum levels of either apo C-II and C-III, whereas only HCV G1b infections caused elevated levels of apo A II and E. Among active HCV infections, HCV G1b was associated with an elevation in the serum apo E levels. Furthermore, IL28B non-major genotype (rs8099917 TG/GG) was associated with low levels of serum apo B and high levels of apoA-II, and advanced fibrosis was associated with low levels of apo B and C-II in G1b infection. CONCLUSIONS Active HCV infection is distinctively associated with characteristic serum apolipoprotein profiles. The influence on apolipoprotein profiles varies with different HCV genotypes. Moreover, the genotype of IL28B and hepatic fibrosis affected serum apolipoproteins in G1b infection. Abnormalities in serum apolipoproteins may provide a clue to the elucidation of complex interactions between active HCV infection and lipid metabolism.
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Shimada N, Tsubota A, Atsukawa M, Abe H, Ika M, Kato K, Sato Y, Kondo C, Sakamoto C, Tanaka Y, Aizawa Y. α-Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir-based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype. J Med Virol 2014; 86:461-72. [PMID: 24166425 DOI: 10.1002/jmv.23824] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2013] [Indexed: 12/14/2022]
Abstract
Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high α-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of-treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low α-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, α-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut-off value of 7.4 ng/ml α-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum α-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C.
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Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
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