Guest guest Posted April 4, 2011 Report Share Posted April 4, 2011 Hepatology. 2011 Mar 30. doi: 10.1002/hep.24327. [Epub ahead of print] Hepatitis C virus targets the T cell secretory machinery as a mechanism of immune evasion. Petrovic D, Stamataki Z, Dempsey E, Golden-Mason L, Freeley M, Doherty D, Prichard D, Keogh C, Conroy J, S, Volkov Y, McKeating JA, O'Farrelly C, Kelleher D, Long A. Dept. of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland. Abstract T-cell activation and the resultant production of interleukin (IL-2) is a central response of the adaptive immune system to pathogens, such as Hepatitis C virus (HCV). HCV utilizes several mechanisms to evade both the innate and adaptive arms of the immune response. Here we demonstrate that liver biopsies from individuals infected with HCV had significantly lower levels of IL-2 compared to those with other inflammatory liver diseases. Cell culture-grown HCV particles (HCVcc) inhibited the production of IL-2 by normal peripheral blood mononuclear cells (PBMCs), as did serum from HCV-infected patients. This process was mediated by the interaction of HCV envelope protein (E2) with tetraspanin CD81 co-receptor. HCV E2 attenuated IL-2 production at the level of secretion and not transcription by targeting the translocation of Protein Kinase C beta (PKCβ), essential for IL-2 secretion, to lipid raft microdomains. The lipid raft disruptor methyl-β-cyclodextrin (MCD) reversed HCV E2-mediated inhibition of IL-2 secretion but not in the presence of a PKCβ-selective inhibitor. HCV E2 further inhibited the secretion of other cytokines including Interferon-γ. Conclusions: these data suggest that HCV E2-mediated disruption of the association of PKCβ with the cellular secretory machinery, represents a novel mechanism for HCV to evade the human immune response and to establish persistent infection. (HEPATOLOGY 2011.).Copyright © 2011 American Association for the Study of Liver Diseases. PMID: 21452285 [PubMed - as supplied by publisher] Hepatology. 2011 Mar 30. doi: 10.1002/hep.24325. [Epub ahead of print] Enhanced T-cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells. Echeverria I, Pereboev A, Silva L, Zabaleta A, Riezu-Boj JI, Bes M, Cubero M, Borras-Cuesta F, Lasarte JJ, Esteban JI, Prieto J, Sarobe P. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Abstract Injection of dendritic cells (DC) presenting viral proteins constitutes a promising approach to stimulate T-cell immunity against hepatitis C virus (HCV). Here we describe a strategy to enhance antigen loading and immunostimulatory functions of DC useful in the preparation of therapeutic vaccines. Incubation of murine DC with CFm40L, an adapter molecule containing the coxsackie-adenovirus receptor fused to the ecto-domain of murine CD40L induced DC maturation, production of high amounts of IL-12 and up-regulation of molecules associated with Th1 responses. Accordingly, targeting of an adenovirus encoding HCV NS3 protein (AdNS3) to DC with CFm40L strongly enhanced NS3 presentation in vitro, activating IFN-γ-producing T-cells. Moreover, immunization of mice with these DC promoted strong CD4 and CD8 T-cell responses against HCV NS3. CFh40L, a similar adapter molecule containing human CD40L, enhanced transduction and maturation of human monocyte-derived DC. Comparison of DC transduced with AdNS3 and CFh40L from patients with chronic HCV infection or healthy donors, showed similar maturation levels. More importantly, DC from the patients induced NS3-specific responses when transduced with AdNS3 and CFh40L but not with AdNS3 alone. Conclusion: DC transduced with AdNS3 and the adapter molecule CFm/h40L exhibit enhanced immunostimulatory functions, induce robust anti-HCV NS3 immunity in animals and can induce antiviral immune responses in subjects with chronic HCV infection. This strategy may serve as therapeutic vaccination for patients with chronic hepatitis C. (HEPATOLOGY 2011.).Copyright © 2011 American Association for the Study of Liver Diseases. PMID: 21452282 [PubMed - as supplied by publisher] Related citations J Hepatol. 2011 Mar 24. [Epub ahead of print] IL28B single nucleotide polymorphisms in the treatment of hepatitis C. Lange CM, Zeuzem S. Klinikum der J. W. Goethe-Universität furt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 furt am Main, Germany; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue Bugnon 46, CH-1010 Lausanne, Switzerland. Abstract Recent genome-wide association studies (GWAS) have identified genetic variations near the IL28B gene which are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. Protective IL28B variations are strongly associated with on-treatment viral kinetics and approximately 2-fold increased sustained virologic response (SVR) rates in HCV genotype 1 and 4 patients. In HCV genotype 1 patients, IL28B variations were shown to be the strongest pre-treatment predictor of virologic response. In the treatment of HCV genotype 2 and 3 infected patients, IL28B variations play only a minor role. Preliminary data indicate that IL28B variations are also associated with treatment outcome of regimens including directly acting antiviral (DAA) agents, though their impact seems to be attenuated compared to standard treatment. Here, we review these important findings and discuss possible implications for clinical decision making in the treatment of HCV infection.Copyright © 2011. Published by Elsevier B.V. PMID: 21440591 [PubMed - as supplied by publisher] J Virol. 2011 Mar 30. [Epub ahead of print] Retention of CD4+CD25+FoxP3+ regulatory T cells in the liver after therapy-induced hepatitis C virus eradication in humans. Claassen MA, de Knegt RJ, Janssen HL, Boonstra A. Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, the Netherlands. Abstract Following infection with the hepatitis C virus (HCV), in most cases immunity fails to eradicate the virus, resulting in slowly progressing immunopathology in the HCV-infected liver. We are the first to examine intrahepatic T cells and CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) in chronic HCV patients during and after antiviral therapy by collecting multiple aspiration biopsies from the liver at different time-points. We found that intrahepatic Treg frequencies were increased upon interferon-α and ribavirin administration in about 50% of chronic HCV patients, suggesting stronger regulation of intrahepatic immunity by Treg during antiviral therapy. After cessation of antiviral therapy, the frequency of intrahepatic Treg remained increased in the large majority of livers of individuals who successfully cleared the virus. The differentiation stage of these Treg that were retained in the liver months after therapy-induced clearance of HCV-RNA, displayed a reduced contribution of effector-memory cells. Our findings, gathered by multiple sampling of the liver, indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of the local immune response to a resting state comparable to healthy livers. The continuous presence of high numbers of Treg, with a phenotype reflecting a relatively weak suppressive activity, suggests ongoing residual regulation of immunopathology. These findings provide important insight in the dynamics of the immune response to HCV, as well as the effect of therapy on intrahepatic immunity. PMID: 21450832 [PubMed - as supplied by publisher] N Engl J Med. 2011 Mar 31;364(13):1207-17. Boceprevir for previously treated chronic HCV genotype 1 infection. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Collaborators (91) Delwaide J, Horsmans Y, Van Vlierberghe H, F, Feinman SV, Heathcote J, Marotta P, Ramji A, Wong F, Peltakian K, Kaita K, Alric L, Ben Ali S, Bigard MA, Bourliere M, Boyer-Darrigrand N, Bronowicki JP, De Ledinghen V, Hezode C, Lebray P, Marcellin P, Maynard-Muet M, Pol S, Poynard T, Tran A, Trepo C, Truchi R, Vallet-Pichard A, Berg T, Guenther R, Lohse AW, Manns MP, Niederau C, Schmidt WE, Spengler U, Wedemeyer H, Zeuzem S, Carosi G, Colombo M, Craxì A, Rizzetto M, Zignego AL, Zuin M, Reymunde A, Buti Ferret M, Esteban R, Afdhal N, Bacon B, Balart L, M, Box T, Boyer T, M, Flamm S, Freilich B, Galati J, Galler G, Gibas A, Godofsky E, Gordon S, Herrera J, Herrine S, son I, King J, Kwo P, Lawitz E, Lee W, Levin J, Luketic V, McCone J, McHutchison J, Mullen K, T, Muir A, Nunes F, Nyberg A, Nyberg L, y MP, Peine C, Ravendhran N, Reindollar R, Riley T, Rossaro L, Rubin R, M, Schiff E, Sherman K, Shiffman M, Strauss R, Vierling J, Yapp R. Saint Louis University School of Medicine, St. Louis, MO 63110-0250, USA. baconbr@... Comment in: N Engl J Med. 2011 Mar 31;364(13):1272-4. Abstract BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.). PMID: 21449784 [PubMed - in process] N Engl J Med. 2011 Mar 31;364(13):1195-206. Boceprevir for untreated chronic HCV genotype 1 infection. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, son IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Collaborators (175) Colombato L, Curciarello J, Silva M, Tanno H, Terg R, Adler M, Langlet P, Lasser L, Nevens F, F, R, Bilodeau M, C, Feinman SV, Heathcote J, Levstik M, Ramji A, Sherman M, Shafran S, Yoshida E, Achim A, Ben Ali S, Bigard MA, Bonny C, Bourliere M, Boyer-Darrigrand N, Bronowicki JP, Canva V, Couzigou P, De Ledinghen V, Guyader D, Hezode C, Larrey D, Latournerie M, Marcellin P, Mathurin P, Maynard-Muet M, Moussalli J, Poupon R, Poynard T, Serfaty L, Tran A, Trepo C, Truchi R, Zarski JP, Berg T, Dikopoulos N, Eisenbach C, Galle PR, Gerken G, Goeser T, Gregor M, Klass D, Kraus MR, Niederau C, Schlaak JF, Schmid R, Thies P, Schmidt K, Thimme R, Weidenbach H, Zeuzem S, Angelico M, Bruno S, Carosi G, Craxì A, Mangia A, Pirisi M, Rizzetto M, Taliani G, Zignego AL, Reesink HW, Serejo F, Reymunde A, do B, E, Barcena Marugan R, De la Mata M, Calleja JL, Castellano G, Diago M, Esteban R, Fernandez- C, Tapias J, Serra Desfilis MA, Afdhal N, Al-Osaimi A, Bacon B, Balart L, M, Bernstein D, Black M, Bowlus C, Boyer T, Dalke D, C, G, M, Everson G, Felizarta F, Flamm S, Freilich B, Galati J, Galler G, Ghalib R, Gibas A, Godofsky E, Gordon F, Gordon S, Gross J, on S, Herrera J, Herrine S, Hu KQ, Imperial J, son I, D, Kilby A, King J, Koch A, Kowdley K, Krawitt E, Kwo P, Lambiase L, Lawitz E, Lee W, Levin J, Levine R, Li X, Lok A, Luketic V, Mailliard M, McCone J, McHutchison J, Mikolich D, T, Muir A, D, Nunes F, Nyberg A, Nyberg L, Pandya P, y MP, Peine C, Poleynard G, Poordad F, Pound D, Poulos J, Rabinovitz M, Ravendhran N, Ready J, Reddy K, Reindollar R, Reuben A, Riley T, Rossaro L, Rubin R, M, Santoro J, Schiff E, Sepe T, Sherman K, Shiffman M, Sjogren M, Sjogren R, C, Stein L, Strauss R, Sulkowski M, Szyjkowski R, Vargas H, Vierling J, Witt D, Yapp R, Younes Z. Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. fred.poordad@... Comment in: N Engl J Med. 2011 Mar 31;364(13):1272-4. Abstract BACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.). PMID: 21449783 [PubMed - in process] Quote Link to comment Share on other sites More sharing options...
Guest guest Posted April 4, 2011 Report Share Posted April 4, 2011 Hepatology. 2011 Mar 30. doi: 10.1002/hep.24327. [Epub ahead of print] Hepatitis C virus targets the T cell secretory machinery as a mechanism of immune evasion. Petrovic D, Stamataki Z, Dempsey E, Golden-Mason L, Freeley M, Doherty D, Prichard D, Keogh C, Conroy J, S, Volkov Y, McKeating JA, O'Farrelly C, Kelleher D, Long A. Dept. of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland. Abstract T-cell activation and the resultant production of interleukin (IL-2) is a central response of the adaptive immune system to pathogens, such as Hepatitis C virus (HCV). HCV utilizes several mechanisms to evade both the innate and adaptive arms of the immune response. Here we demonstrate that liver biopsies from individuals infected with HCV had significantly lower levels of IL-2 compared to those with other inflammatory liver diseases. Cell culture-grown HCV particles (HCVcc) inhibited the production of IL-2 by normal peripheral blood mononuclear cells (PBMCs), as did serum from HCV-infected patients. This process was mediated by the interaction of HCV envelope protein (E2) with tetraspanin CD81 co-receptor. HCV E2 attenuated IL-2 production at the level of secretion and not transcription by targeting the translocation of Protein Kinase C beta (PKCβ), essential for IL-2 secretion, to lipid raft microdomains. The lipid raft disruptor methyl-β-cyclodextrin (MCD) reversed HCV E2-mediated inhibition of IL-2 secretion but not in the presence of a PKCβ-selective inhibitor. HCV E2 further inhibited the secretion of other cytokines including Interferon-γ. Conclusions: these data suggest that HCV E2-mediated disruption of the association of PKCβ with the cellular secretory machinery, represents a novel mechanism for HCV to evade the human immune response and to establish persistent infection. (HEPATOLOGY 2011.).Copyright © 2011 American Association for the Study of Liver Diseases. PMID: 21452285 [PubMed - as supplied by publisher] Hepatology. 2011 Mar 30. doi: 10.1002/hep.24325. [Epub ahead of print] Enhanced T-cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells. Echeverria I, Pereboev A, Silva L, Zabaleta A, Riezu-Boj JI, Bes M, Cubero M, Borras-Cuesta F, Lasarte JJ, Esteban JI, Prieto J, Sarobe P. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Abstract Injection of dendritic cells (DC) presenting viral proteins constitutes a promising approach to stimulate T-cell immunity against hepatitis C virus (HCV). Here we describe a strategy to enhance antigen loading and immunostimulatory functions of DC useful in the preparation of therapeutic vaccines. Incubation of murine DC with CFm40L, an adapter molecule containing the coxsackie-adenovirus receptor fused to the ecto-domain of murine CD40L induced DC maturation, production of high amounts of IL-12 and up-regulation of molecules associated with Th1 responses. Accordingly, targeting of an adenovirus encoding HCV NS3 protein (AdNS3) to DC with CFm40L strongly enhanced NS3 presentation in vitro, activating IFN-γ-producing T-cells. Moreover, immunization of mice with these DC promoted strong CD4 and CD8 T-cell responses against HCV NS3. CFh40L, a similar adapter molecule containing human CD40L, enhanced transduction and maturation of human monocyte-derived DC. Comparison of DC transduced with AdNS3 and CFh40L from patients with chronic HCV infection or healthy donors, showed similar maturation levels. More importantly, DC from the patients induced NS3-specific responses when transduced with AdNS3 and CFh40L but not with AdNS3 alone. Conclusion: DC transduced with AdNS3 and the adapter molecule CFm/h40L exhibit enhanced immunostimulatory functions, induce robust anti-HCV NS3 immunity in animals and can induce antiviral immune responses in subjects with chronic HCV infection. This strategy may serve as therapeutic vaccination for patients with chronic hepatitis C. (HEPATOLOGY 2011.).Copyright © 2011 American Association for the Study of Liver Diseases. PMID: 21452282 [PubMed - as supplied by publisher] Related citations J Hepatol. 2011 Mar 24. [Epub ahead of print] IL28B single nucleotide polymorphisms in the treatment of hepatitis C. Lange CM, Zeuzem S. Klinikum der J. W. Goethe-Universität furt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 furt am Main, Germany; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue Bugnon 46, CH-1010 Lausanne, Switzerland. Abstract Recent genome-wide association studies (GWAS) have identified genetic variations near the IL28B gene which are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. Protective IL28B variations are strongly associated with on-treatment viral kinetics and approximately 2-fold increased sustained virologic response (SVR) rates in HCV genotype 1 and 4 patients. In HCV genotype 1 patients, IL28B variations were shown to be the strongest pre-treatment predictor of virologic response. In the treatment of HCV genotype 2 and 3 infected patients, IL28B variations play only a minor role. Preliminary data indicate that IL28B variations are also associated with treatment outcome of regimens including directly acting antiviral (DAA) agents, though their impact seems to be attenuated compared to standard treatment. Here, we review these important findings and discuss possible implications for clinical decision making in the treatment of HCV infection.Copyright © 2011. Published by Elsevier B.V. PMID: 21440591 [PubMed - as supplied by publisher] J Virol. 2011 Mar 30. [Epub ahead of print] Retention of CD4+CD25+FoxP3+ regulatory T cells in the liver after therapy-induced hepatitis C virus eradication in humans. Claassen MA, de Knegt RJ, Janssen HL, Boonstra A. Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, the Netherlands. Abstract Following infection with the hepatitis C virus (HCV), in most cases immunity fails to eradicate the virus, resulting in slowly progressing immunopathology in the HCV-infected liver. We are the first to examine intrahepatic T cells and CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) in chronic HCV patients during and after antiviral therapy by collecting multiple aspiration biopsies from the liver at different time-points. We found that intrahepatic Treg frequencies were increased upon interferon-α and ribavirin administration in about 50% of chronic HCV patients, suggesting stronger regulation of intrahepatic immunity by Treg during antiviral therapy. After cessation of antiviral therapy, the frequency of intrahepatic Treg remained increased in the large majority of livers of individuals who successfully cleared the virus. The differentiation stage of these Treg that were retained in the liver months after therapy-induced clearance of HCV-RNA, displayed a reduced contribution of effector-memory cells. Our findings, gathered by multiple sampling of the liver, indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of the local immune response to a resting state comparable to healthy livers. The continuous presence of high numbers of Treg, with a phenotype reflecting a relatively weak suppressive activity, suggests ongoing residual regulation of immunopathology. These findings provide important insight in the dynamics of the immune response to HCV, as well as the effect of therapy on intrahepatic immunity. PMID: 21450832 [PubMed - as supplied by publisher] N Engl J Med. 2011 Mar 31;364(13):1207-17. Boceprevir for previously treated chronic HCV genotype 1 infection. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Collaborators (91) Delwaide J, Horsmans Y, Van Vlierberghe H, F, Feinman SV, Heathcote J, Marotta P, Ramji A, Wong F, Peltakian K, Kaita K, Alric L, Ben Ali S, Bigard MA, Bourliere M, Boyer-Darrigrand N, Bronowicki JP, De Ledinghen V, Hezode C, Lebray P, Marcellin P, Maynard-Muet M, Pol S, Poynard T, Tran A, Trepo C, Truchi R, Vallet-Pichard A, Berg T, Guenther R, Lohse AW, Manns MP, Niederau C, Schmidt WE, Spengler U, Wedemeyer H, Zeuzem S, Carosi G, Colombo M, Craxì A, Rizzetto M, Zignego AL, Zuin M, Reymunde A, Buti Ferret M, Esteban R, Afdhal N, Bacon B, Balart L, M, Box T, Boyer T, M, Flamm S, Freilich B, Galati J, Galler G, Gibas A, Godofsky E, Gordon S, Herrera J, Herrine S, son I, King J, Kwo P, Lawitz E, Lee W, Levin J, Luketic V, McCone J, McHutchison J, Mullen K, T, Muir A, Nunes F, Nyberg A, Nyberg L, y MP, Peine C, Ravendhran N, Reindollar R, Riley T, Rossaro L, Rubin R, M, Schiff E, Sherman K, Shiffman M, Strauss R, Vierling J, Yapp R. Saint Louis University School of Medicine, St. Louis, MO 63110-0250, USA. baconbr@... Comment in: N Engl J Med. 2011 Mar 31;364(13):1272-4. Abstract BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.). PMID: 21449784 [PubMed - in process] N Engl J Med. 2011 Mar 31;364(13):1195-206. Boceprevir for untreated chronic HCV genotype 1 infection. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, son IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Collaborators (175) Colombato L, Curciarello J, Silva M, Tanno H, Terg R, Adler M, Langlet P, Lasser L, Nevens F, F, R, Bilodeau M, C, Feinman SV, Heathcote J, Levstik M, Ramji A, Sherman M, Shafran S, Yoshida E, Achim A, Ben Ali S, Bigard MA, Bonny C, Bourliere M, Boyer-Darrigrand N, Bronowicki JP, Canva V, Couzigou P, De Ledinghen V, Guyader D, Hezode C, Larrey D, Latournerie M, Marcellin P, Mathurin P, Maynard-Muet M, Moussalli J, Poupon R, Poynard T, Serfaty L, Tran A, Trepo C, Truchi R, Zarski JP, Berg T, Dikopoulos N, Eisenbach C, Galle PR, Gerken G, Goeser T, Gregor M, Klass D, Kraus MR, Niederau C, Schlaak JF, Schmid R, Thies P, Schmidt K, Thimme R, Weidenbach H, Zeuzem S, Angelico M, Bruno S, Carosi G, Craxì A, Mangia A, Pirisi M, Rizzetto M, Taliani G, Zignego AL, Reesink HW, Serejo F, Reymunde A, do B, E, Barcena Marugan R, De la Mata M, Calleja JL, Castellano G, Diago M, Esteban R, Fernandez- C, Tapias J, Serra Desfilis MA, Afdhal N, Al-Osaimi A, Bacon B, Balart L, M, Bernstein D, Black M, Bowlus C, Boyer T, Dalke D, C, G, M, Everson G, Felizarta F, Flamm S, Freilich B, Galati J, Galler G, Ghalib R, Gibas A, Godofsky E, Gordon F, Gordon S, Gross J, on S, Herrera J, Herrine S, Hu KQ, Imperial J, son I, D, Kilby A, King J, Koch A, Kowdley K, Krawitt E, Kwo P, Lambiase L, Lawitz E, Lee W, Levin J, Levine R, Li X, Lok A, Luketic V, Mailliard M, McCone J, McHutchison J, Mikolich D, T, Muir A, D, Nunes F, Nyberg A, Nyberg L, Pandya P, y MP, Peine C, Poleynard G, Poordad F, Pound D, Poulos J, Rabinovitz M, Ravendhran N, Ready J, Reddy K, Reindollar R, Reuben A, Riley T, Rossaro L, Rubin R, M, Santoro J, Schiff E, Sepe T, Sherman K, Shiffman M, Sjogren M, Sjogren R, C, Stein L, Strauss R, Sulkowski M, Szyjkowski R, Vargas H, Vierling J, Witt D, Yapp R, Younes Z. Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. fred.poordad@... Comment in: N Engl J Med. 2011 Mar 31;364(13):1272-4. Abstract BACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.). PMID: 21449783 [PubMed - in process] Quote Link to comment Share on other sites More sharing options...
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