Guest guest Posted January 29, 2011 Report Share Posted January 29, 2011 J Infect Dis. 2011 Jan 21. [Epub ahead of print] Genetic Variation in IL28B and Treatment-Induced Clearance of Hepatitis C Virus in HIV-Positive Patients With Acute and Chronic Hepatitis C. Nattermann J, Vogel M, Nischalke HD, Danta M, Mauss S, Stellbrink HJ, Baumgarten A, Mayr C, Bruno R, Tural C, Klausen G, Clotet B, Naumann U, Lutz T, Rausch M, Schewe K, Bienek B, Haerter G, Sauerbruch T, Rockstroh JK, Spengler U. Department of Internal Medicine I, University of Bonn, Bonn. Abstract Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatits C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C. PMID: 21257738 [PubMed - as supplied by publisher] Related citations 32. J Infect Dis. 2011 Jan 21. [Epub ahead of print] Strong Hepatitis C Virus (HCV)-specific Cell-mediated Immune Responses in the Absence of Viremia or Antibodies Among Uninfected Siblings of HCV Chronically Infected Children. Hashem M, El-Karaksy H, Shata MT, Sobhy M, Helmy H, El-Naghi S, Galal G, Ali ZZ, Esmat G, Abdelwahab SF, Strickland GT, El-Kamary SS. Department of Epidemiology and Public Health, University of land School of Medicine, Baltimore, land. Abstract Background. Cell-mediated immune (CMI) responses to hepatitis C virus (HCV) antigens in adults without seroconversion or viremia are biomarkers for prior transient infection. We investigated HCV-specific CMI responses in seronegative children living with HCV-infected siblings. Methods. Children 3-18 years of age living with HCV-infected siblings were screened for HCV antibodies and HCV RNA. Peripheral blood mononuclear cells (PBMCs) were evaluated for HCV-specific CMI responses by interferon γ (IFN-γ) enzyme-linked immunospot assay using 3 recombinant HCV protein antigens. Flow cytometry phenotypically characterized IFN-γ-secreting cells. Results. Forty-five seronegative children and 5 seropositive viremic siblings had functionally viable PBMCs. Among the 45 seronegative siblings, 15 (33.3%) had positive HCV-specific IFN-γ responses, and subsequent RNA testing revealed that 3 were viremic. Compared with the 5 seropositive viremic children, the median number of HCV-specific spot-forming units was significantly higher in the 12 seronegative aviremic children (P = ..002) and in the 3 seronegative viremic children (P = .025). Flow cytometric analysis revealed that IFN-γ was synthesized mainly by CD4(+) T cells. Conclusion. Strong HCV-specific CD4(+) T cell responses were detectable in higher frequency among seronegative, aviremic children compared with persistently infected siblings. Further studies are needed to determine whether these immune responses are protective against HCV infection. PMID: 21257736 [PubMed - as supplied by publisher] Related citations 33. J Med Virol. 2011 Mar;83(3):445-52. doi: 10.1002/jmv.22005. Sequences in the interferon sensitivity-determining region and core region of hepatitis C virus impact pretreatment prediction of response to PEG-interferon plus ribavirin: Data mining analysis. Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Hiramatsu N, Sugauchi F, Tamori A, Nakagawa M, Izumi N. Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan. Abstract The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity-determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG-IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P = 0.01) predicted sustained virological response independent of other covariates. The decision-tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0-1) but was 83% in selected subgroups of younger patients (<60 years), wild-type sequence at Core70, and higher level of low-density lipoprotein cholesterol (LDL-C) (≥120 mg/dl). Reproducibility of the model was validated (r(2)  = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG-IFN plus RBV therapy. A decision-tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response. J. Med. Virol. 83:445-452, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264865 [PubMed - in process] Related citations 34. J Med Virol. 2011 Mar;83(3):437-44. doi: 10.1002/jmv.21976. Influence of HCV genotype 1 subtypes on the virus response to PEG interferon alpha-2a plus ribavirin therapy. Nicot F, Alric L, Barange K, Métivier S, Dramard JM, Combis JM, Castan B, Meurisse JJ, Payen JL, Garipuy D, Desmorat H, Peron JM, Thebault S, Morin T, Renou C, Barel P, Guerin B, Imbert Y, Sire S, Sauné K, Chatelut E, Izopet J. CHU Toulouse, IFB Purpan, Laboratoire de Virologie, Toulouse, France. Abstract New factors that influence the viral response in HCV non-genotype 2/3 patients must be identified in order to optimize anti-HCV treatment. This multicenter prospective study evaluates the influence of HCV variability and pharmacological parameters on the virological response of these patients to pegylated interferon α2a (peg-IFN-α2a: 180 µg/week) and ribavirin (RBV; 800-1,200 mg/day) for 48 weeks. HCV subtypes were identified by sequencing the NS5B region. Serum RBV and peg-IFN-α2a concentrations were measured at weeks 4 and 12. The 115 patients (67 men; median age = 49, range 31-76) included 64 who had never been treated and 27 co-infected with HIV. The mean baseline HCV RNA was 6.30 ± 0.06 log IU/ml and the HCV genotypes were: G1 (n = 93) with 1a (n = 37) and 1b (n = 50), G4 (n = 20) and G5 (n = 2). Most patients (79/108; 73%) had an early virological response. Independent predictors of an early virological response were interferon naive patients (OR = 2.98, 95% CI: 1.15-7.72) and RBV of >2,200 ng/ml at week 12 (OR = 3.41, 95% CI: 1.31-8.90). Forty of 104 patients (38%) had a sustained virological response. The only independent predictors of a sustained virological response were subtype 1b (OR = 6.82, 95% CI: 1.7-26.8), and HCV RNA <15 IU/ml at week 12 (OR = 25, 95% CI: 6.4-97.6). Thus a serum RBV concentration of >2,200 ng/ml was associated with an early virological response and patients infected with HCV subtype 1b had a better chance of a sustained virological response than did those infected with subtype 1a. J. Med. Virol. 83:437-444, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264864 [PubMed - in process] Related citations 35. J Med Virol. 2011 Mar;83(3):428-36. doi: 10.1002/jmv.21983. Phylogenetic investigation of nosocomial transmission of hepatitis C virus in an oncology ward. Dencs A, Hettmann A, Martyin T, Jekkel C, Bányai T, Takács M. Division of Virology, National Center for Epidemiology, Budapest, Hungary. Abstract Nosocomial hepatitis C virus (HCV) infections have been reported from different health-care settings worldwide. Twenty patients, treated at the same oncology department, with no previous record of hepatitis C infection, tested positive for anti-HCV antibodies between November 2007 and June 2008. Twelve of the newly infected patients were found to be HCV RNA positive. The common origin of the infections was assumed. To investigate the relatedness of the detected viral strains phylogenetic analyses were performed using sequences from the NS5B and E1/E2 genome regions. A patient carrying HCV for years was also involved in the study. She was treated at the same oncology department and was considered a possible infectious source. The previous HCV carrier harbored subtype 1b, while all other patients were infected with subtype 1a. Sequences from the 12 newly infected patients formed two groups. The viral sequences within the groups were very closely related. A greater evolutionary distance was observed between the two groups; however, their relatedness could be demonstrated by sequences from both regions with high statistical support. The results indicated that nosocomial transmission occurred. The phylogenetic analyses suggested that the viruses originated from a common source, possibly a patient carrying highly divergent variants. This presumed infectious source could not be identified in the course of this study. The genotype distribution of Hungarian control sequences included in the analysis confirmed this conclusion, since HCV genotype 1a was found to be relatively uncommon. J. Med. Virol. 83:428-436, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264863 [PubMed - in process] Related citations J Med Virol. 2011 Mar;83(3):419-27. doi: 10.1002/jmv.21975. Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin. Inoue Y, Hiramatsu N, Oze T, Yakushijin T, Mochizuki K, Fukuda K, Mita E, Haruna Y, Inoue A, Imai Y, Hosui A, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Takehara T, Hayashi N. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan. Abstract Previous reports demonstrated that amino acid (aa) substitutions in the hepatitis C virus (HCV) core protein are predictors of non-virological responses to pegylated interferon (Peg-IFN) and ribavirin combination therapy. The aim of this study was to investigate the impact of core aa substitutions on viral kinetics during the treatment and relapse after the treatment. The 187 patients with HCV genotype 1 enrolled in this study were categorized into four groups according to core aa substitution patterns: double-wild group (n = 92), Arg70/Leu91; 70-mutant group (n = 42), Gln70/Leu91; 91-mutant group (n = 31), Arg70/Met91; and double-mutant group (n = 22), Gln70/Met91. The relationship between the core aa substitutions and the virological response was examined. Multivariate logistic regression analyses showed that substitution at aa 70 was significantly associated with a poor virological response during the first 12 weeks (decline of <1 log from baseline at week 4, <2 log at week 12), and substitution at aa 91 was significantly associated with detectable HCV RNA at week 24. With respect to relapse, only the ribavirin exposure (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.60-0.98) and HCV RNA disappearance between weeks 13 and 24 (OR, 23.69; 95% CI, 5.44-103.08) were associated independently with relapse, with no correlation being found with the core aa substitutions and relapse. In conclusion, the results showed that core aa substitutions can be strong predictive factors at pretreatment of the non-response, but not for relapse, for virological responders with HCV RNA disappearance during treatment. J. Med. Virol. 83:419-427, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264862 [PubMed - in process] Related citations Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 29, 2011 Report Share Posted January 29, 2011 J Infect Dis. 2011 Jan 21. [Epub ahead of print] Genetic Variation in IL28B and Treatment-Induced Clearance of Hepatitis C Virus in HIV-Positive Patients With Acute and Chronic Hepatitis C. Nattermann J, Vogel M, Nischalke HD, Danta M, Mauss S, Stellbrink HJ, Baumgarten A, Mayr C, Bruno R, Tural C, Klausen G, Clotet B, Naumann U, Lutz T, Rausch M, Schewe K, Bienek B, Haerter G, Sauerbruch T, Rockstroh JK, Spengler U. Department of Internal Medicine I, University of Bonn, Bonn. Abstract Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatits C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C. PMID: 21257738 [PubMed - as supplied by publisher] Related citations 32. J Infect Dis. 2011 Jan 21. [Epub ahead of print] Strong Hepatitis C Virus (HCV)-specific Cell-mediated Immune Responses in the Absence of Viremia or Antibodies Among Uninfected Siblings of HCV Chronically Infected Children. Hashem M, El-Karaksy H, Shata MT, Sobhy M, Helmy H, El-Naghi S, Galal G, Ali ZZ, Esmat G, Abdelwahab SF, Strickland GT, El-Kamary SS. Department of Epidemiology and Public Health, University of land School of Medicine, Baltimore, land. Abstract Background. Cell-mediated immune (CMI) responses to hepatitis C virus (HCV) antigens in adults without seroconversion or viremia are biomarkers for prior transient infection. We investigated HCV-specific CMI responses in seronegative children living with HCV-infected siblings. Methods. Children 3-18 years of age living with HCV-infected siblings were screened for HCV antibodies and HCV RNA. Peripheral blood mononuclear cells (PBMCs) were evaluated for HCV-specific CMI responses by interferon γ (IFN-γ) enzyme-linked immunospot assay using 3 recombinant HCV protein antigens. Flow cytometry phenotypically characterized IFN-γ-secreting cells. Results. Forty-five seronegative children and 5 seropositive viremic siblings had functionally viable PBMCs. Among the 45 seronegative siblings, 15 (33.3%) had positive HCV-specific IFN-γ responses, and subsequent RNA testing revealed that 3 were viremic. Compared with the 5 seropositive viremic children, the median number of HCV-specific spot-forming units was significantly higher in the 12 seronegative aviremic children (P = ..002) and in the 3 seronegative viremic children (P = .025). Flow cytometric analysis revealed that IFN-γ was synthesized mainly by CD4(+) T cells. Conclusion. Strong HCV-specific CD4(+) T cell responses were detectable in higher frequency among seronegative, aviremic children compared with persistently infected siblings. Further studies are needed to determine whether these immune responses are protective against HCV infection. PMID: 21257736 [PubMed - as supplied by publisher] Related citations 33. J Med Virol. 2011 Mar;83(3):445-52. doi: 10.1002/jmv.22005. Sequences in the interferon sensitivity-determining region and core region of hepatitis C virus impact pretreatment prediction of response to PEG-interferon plus ribavirin: Data mining analysis. Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Hiramatsu N, Sugauchi F, Tamori A, Nakagawa M, Izumi N. Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan. Abstract The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity-determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG-IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P = 0.01) predicted sustained virological response independent of other covariates. The decision-tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0-1) but was 83% in selected subgroups of younger patients (<60 years), wild-type sequence at Core70, and higher level of low-density lipoprotein cholesterol (LDL-C) (≥120 mg/dl). Reproducibility of the model was validated (r(2)  = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG-IFN plus RBV therapy. A decision-tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response. J. Med. Virol. 83:445-452, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264865 [PubMed - in process] Related citations 34. J Med Virol. 2011 Mar;83(3):437-44. doi: 10.1002/jmv.21976. Influence of HCV genotype 1 subtypes on the virus response to PEG interferon alpha-2a plus ribavirin therapy. Nicot F, Alric L, Barange K, Métivier S, Dramard JM, Combis JM, Castan B, Meurisse JJ, Payen JL, Garipuy D, Desmorat H, Peron JM, Thebault S, Morin T, Renou C, Barel P, Guerin B, Imbert Y, Sire S, Sauné K, Chatelut E, Izopet J. CHU Toulouse, IFB Purpan, Laboratoire de Virologie, Toulouse, France. Abstract New factors that influence the viral response in HCV non-genotype 2/3 patients must be identified in order to optimize anti-HCV treatment. This multicenter prospective study evaluates the influence of HCV variability and pharmacological parameters on the virological response of these patients to pegylated interferon α2a (peg-IFN-α2a: 180 µg/week) and ribavirin (RBV; 800-1,200 mg/day) for 48 weeks. HCV subtypes were identified by sequencing the NS5B region. Serum RBV and peg-IFN-α2a concentrations were measured at weeks 4 and 12. The 115 patients (67 men; median age = 49, range 31-76) included 64 who had never been treated and 27 co-infected with HIV. The mean baseline HCV RNA was 6.30 ± 0.06 log IU/ml and the HCV genotypes were: G1 (n = 93) with 1a (n = 37) and 1b (n = 50), G4 (n = 20) and G5 (n = 2). Most patients (79/108; 73%) had an early virological response. Independent predictors of an early virological response were interferon naive patients (OR = 2.98, 95% CI: 1.15-7.72) and RBV of >2,200 ng/ml at week 12 (OR = 3.41, 95% CI: 1.31-8.90). Forty of 104 patients (38%) had a sustained virological response. The only independent predictors of a sustained virological response were subtype 1b (OR = 6.82, 95% CI: 1.7-26.8), and HCV RNA <15 IU/ml at week 12 (OR = 25, 95% CI: 6.4-97.6). Thus a serum RBV concentration of >2,200 ng/ml was associated with an early virological response and patients infected with HCV subtype 1b had a better chance of a sustained virological response than did those infected with subtype 1a. J. Med. Virol. 83:437-444, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264864 [PubMed - in process] Related citations 35. J Med Virol. 2011 Mar;83(3):428-36. doi: 10.1002/jmv.21983. Phylogenetic investigation of nosocomial transmission of hepatitis C virus in an oncology ward. Dencs A, Hettmann A, Martyin T, Jekkel C, Bányai T, Takács M. Division of Virology, National Center for Epidemiology, Budapest, Hungary. Abstract Nosocomial hepatitis C virus (HCV) infections have been reported from different health-care settings worldwide. Twenty patients, treated at the same oncology department, with no previous record of hepatitis C infection, tested positive for anti-HCV antibodies between November 2007 and June 2008. Twelve of the newly infected patients were found to be HCV RNA positive. The common origin of the infections was assumed. To investigate the relatedness of the detected viral strains phylogenetic analyses were performed using sequences from the NS5B and E1/E2 genome regions. A patient carrying HCV for years was also involved in the study. She was treated at the same oncology department and was considered a possible infectious source. The previous HCV carrier harbored subtype 1b, while all other patients were infected with subtype 1a. Sequences from the 12 newly infected patients formed two groups. The viral sequences within the groups were very closely related. A greater evolutionary distance was observed between the two groups; however, their relatedness could be demonstrated by sequences from both regions with high statistical support. The results indicated that nosocomial transmission occurred. The phylogenetic analyses suggested that the viruses originated from a common source, possibly a patient carrying highly divergent variants. This presumed infectious source could not be identified in the course of this study. The genotype distribution of Hungarian control sequences included in the analysis confirmed this conclusion, since HCV genotype 1a was found to be relatively uncommon. J. Med. Virol. 83:428-436, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264863 [PubMed - in process] Related citations J Med Virol. 2011 Mar;83(3):419-27. doi: 10.1002/jmv.21975. Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin. Inoue Y, Hiramatsu N, Oze T, Yakushijin T, Mochizuki K, Fukuda K, Mita E, Haruna Y, Inoue A, Imai Y, Hosui A, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Takehara T, Hayashi N. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan. Abstract Previous reports demonstrated that amino acid (aa) substitutions in the hepatitis C virus (HCV) core protein are predictors of non-virological responses to pegylated interferon (Peg-IFN) and ribavirin combination therapy. The aim of this study was to investigate the impact of core aa substitutions on viral kinetics during the treatment and relapse after the treatment. The 187 patients with HCV genotype 1 enrolled in this study were categorized into four groups according to core aa substitution patterns: double-wild group (n = 92), Arg70/Leu91; 70-mutant group (n = 42), Gln70/Leu91; 91-mutant group (n = 31), Arg70/Met91; and double-mutant group (n = 22), Gln70/Met91. The relationship between the core aa substitutions and the virological response was examined. Multivariate logistic regression analyses showed that substitution at aa 70 was significantly associated with a poor virological response during the first 12 weeks (decline of <1 log from baseline at week 4, <2 log at week 12), and substitution at aa 91 was significantly associated with detectable HCV RNA at week 24. With respect to relapse, only the ribavirin exposure (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.60-0.98) and HCV RNA disappearance between weeks 13 and 24 (OR, 23.69; 95% CI, 5.44-103.08) were associated independently with relapse, with no correlation being found with the core aa substitutions and relapse. In conclusion, the results showed that core aa substitutions can be strong predictive factors at pretreatment of the non-response, but not for relapse, for virological responders with HCV RNA disappearance during treatment. J. Med. Virol. 83:419-427, 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. PMID: 21264862 [PubMed - in process] Related citations Quote Link to comment Share on other sites More sharing options...
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