Accepted Article
Received Date : 04-Feb-2015 Revised Date : 05-Feb-2015 Accepted Date : 06-Feb-2015 Article type
: Editorial
Towards personalized medicine in chronic HBV patients?
Author: Giovanni Sitia
Affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Correspondence should be addressed to: Giovanni Sitia, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy; Tel.: +39-02-2643-4956 FAX: +39-02-2643-6822.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12806 This article is protected by copyright. All rights reserved.
Accepted Article
Email: [email protected]
Abbreviations: HBV, Hepatitis B virus; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; NUCs, nucleos(t)ide analogues; Peg-IFN, pegylated interferon-α; cccDNA, covalently closed circular DNA; HBsAg, hepatitis B surface antigen; ALT, alanine aminotransferase. Conflict of interest: Nothing to declare.
Hepatitis B virus (HBV) is an hepatotropic DNA virus that infects only humans and chimpanzees causing acute and chronic liver disease. More than 350 million people worldwide have chronic hepatitis B (CHB), with almost 1 million deaths directly ascribable to the complication of chronic infection, e.g., liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) (1, 2). Since HBV does not cause direct hepatocellular damage, liver disease during CHB mainly results from repetitive cycles of immune mediated cell injury that are followed by secondary hepatocellular regeneration and liver repair processes in an endless and ineffective attempt to permanently eliminate the virus and restore anatomical and functional organ integrity (3). Overtime, chronic hepatocellular injury and its consequences put CHB patients at a great risk of developing liver fibrosis/cirrhosis and HCC (3).
Available antiviral therapies for CHB patients consist of nucleos(t)ide analogues (NUCs) - i.e. lamivudine, adefovir, entecavir, telbuvidine and tenofovir - which directly suppress HBV replication and/or pegylated interferon-α (Peg-IFN), which possesses both antiviral and immune regulatory functions (2).
This article is protected by copyright. All rights reserved.
Accepted Article
As potent inhibitors of the HBV polymerase, NUCs have been previously shown to reduce hepatocellular damage and to promote histological reversion of liver fibrosis/cirrhosis (4), although their effectiveness at containing the risk of HCC development remains questionable (5, 6). Unfortunately, a large fraction of chronically infected patients do not respond to NUCs with permanent elimination of HBV. Besides the difficulty of sustaining the costs of treatment, this is because of different reasons. First, all NUCs have an intrinsic limited efficacy as they do not target the HBV covalently closed circular DNA (cccDNA) - the template of viral transcription that resides episomally in the nucleus of the infected hepatocyte - which is thought to have a long half-life. As such, the likelihood of viral rebounds following treatment withdrawal remains quite high (7). Second, dose-limiting side effects and emergence of drug-resistant mutants, particularly in the case of first-generation NUCs, further limit the capacity of these molecules to completely eliminate the virus (8). In keeping with what mentioned above, NUC therapy rarely achieves loss of circulating hepatitis B surface antigen (HBsAg), which is a conceivable marker of cccDNA clearance and it is commonly considered the closest endpoint of sustained viral control (2). By contrast, therapy with Peg-IFN has the potential to induce antiviral and immunemediated functions that are curative of cccDNA and, therefore, it represents the only existing chance for sustained off-treatment responses. These apparent benefits are limited, however, to a minority of patients. In addition to associated side effects, factors that influence response rates to Peg-IFN therapy and currently guide clinical practice include age, relatively high alanine aminotransferase (ALT) levels, low viral load and infection with specific HBV genotypes (2, 9). Currently, there are no biomarkers able to predict the course of NUC or Peg-IFN therapy. Thus, unnecessary use of therapy in patients destined not to respond often occurs, resulting in overall unsatisfactory response rates.
Accepted Article
In this issue of Liver International, Jansen et al. identified a specific intrahepatic gene signature able to distinguish outcome of therapy (responders vs. non-responders) in CHB patients treated with adefovir and Peg-IFN (10). In particular, the authors utilized pre-treatment core-needle liver biopsies, to show that a group of genes related to the adaptive immune response - more specifically to antigen processing and presentation or leucocyte chemotaxis - are up-regulated in patients that ultimately responded to therapy (10). Conversely, this same pre-treatment intrahepatic signature appears not to be present in patients that failed to respond to therapy. The authors also realized that a variety of the up-regulated genes resemble the typical gene signature previously described in the liver of chimpanzees during the resolution phase of an acute HBV infection (11). To this regard, previous studies in acutely infected chimpanzees have shown that the innate immune response seems not to contribute significantly to the pathogenesis of liver disease or viral clearance (e.g., little or no induction of innate immune genes and/or IFN-responsive genes is observed in the liver of these animals before T cells enter the liver), while the adaptive immune response, especially the virus-specific effector CD8+ T cell response, contributes to both (e.g., a strong induction of not only IFN-responsive genes but also genes linked to antigen processing and presentation or leucocyte chemotaxis is observed in the chimp liver as T cells start entering the liver) (11). The importance of CD8+ T cells in the control of HBV is also highlighted by additional chimp studies in which the depletion of CD8+ T cells at the peak of HBV replication was shown to delay liver immunopathology and inhibit viral clearance (12). Based on these notions, it is evident that CD8+ T cell effector functions promote the resolution of HBV infection and that viral persistence results from the failure to induce or maintain these CD8+ T cell-dependent events.
In this context, the results of Jansen et al suggest that a pre-existing intrahepatic HBV-specific adaptive immune response, albeit dysfunctional and not sufficient to spontaneously clear the
This article is protected by copyright. All rights reserved.
Accepted Article
virus, is necessary for therapy-induced long-term control of HBV, in particular in the case of adefovir and Peg-IFN combination therapy. Future studies analyzing pre-treatment liver gene expression profiles are needed to understand whether similar or different results will be obtained in cohorts of patients receiving more potent NUCs with higher genetic barrier alone or in combination with Peg-IFN. Of note, the basic concept of pre-existing adaptive immune responses regulating treatment outcome fits with previous studies in which the relative extent of therapy responsiveness was measured against number and function of HBV-specific T cells circulating in blood before treatment initiation (13-15).
All in all, the results presented by Jansen et al. suggest a novel and personalized approach to
anti-viral therapy in CHB patients, where pre-treatment analyses of specific immunological gene signatures may help decisions to treatment. In this scenario, patients with immunological gene signatures associated with a sustained response to a particular therapy (should this be based on NUCs, Peg-IFN or both) might be directed towards specific therapeutic avenues with obvious benefit for the patient and health care systems at large. Clearly, much more work needs to be done in the trail designed by Jansen et al. This includes: i) the necessity of extending such analyses to large cohorts of patients that undergo different antiviral therapies; ii) the evaluation of analyzing genetically fine-needle aspiration biopsies instead of core-needle biopsies (thus rendering the sampling less risky and more attainable in the day-to-day clinical practice) and iii) the assessment of results coming from arrays composed of limited sets of predictive genes (thus rendering the genetic procedure more affordable). Patients, physicians and heath care providers await with hope.
Accepted Article
Acknowledgments I thank Luca G. Guidotti for critical reading of this manuscript. This work was partially supported by grant RF11.61 from the Italian Ministry of Health.
Figure Legend
Fig. 1 Towards personalized medicine in chronic HBV patients After liver biopsy and gene expression profiling, chronic HBV patients are stratified and directed to specific antiviral therapies. The figure was generated with images from Servier Medical Art (www.servier.com), licensed under the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/license/by/3.0/).
This article is protected by copyright. All rights reserved.
Accepted Article
References
1.
Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences.
N Engl J Med. 2004;350(11):1118-29. 2.
European Association For The Study Of The Liver. EASL clinical practice guidelines:
Management of chronic hepatitis B virus infection. Journal of hepatology. 2012;57(1):167-85. 3.
Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annual review
of pathology. 2006;1:23-61. 4.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis
during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75. 5.
Pellicelli AM, Vignally P, Messina V, Izzi A, Mazzoni E, Barlattani A, et al. Long term
nucleotide and nucleoside analogs treatment in chronic hepatitis B HBeAg negative genotype D patients and risk for hepatocellular carcinoma. Annals of hepatology. 2014;13(4):376-85.
6.
Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P. Risk of Hepatocellular
Carcinoma in Chronic Hepatitis B: Assessment and Modification With Current Antiviral Therapy. Journal of hepatology. 2015. 7.
Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus
infections: towards restoration of immune control of viral infection. Gut. 2012;61(12):1754-64. 8.
Zoulim F, Buti M, Lok AS. Antiviral-resistant hepatitis B virus: can we prevent this monster
from growing? Journal of viral hepatitis. 2007;14 Suppl 1:29-36.
Accepted Article
9.
Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, et al. Factors that
predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferonalfa. Gastroenterology. 2009;137(6):2002-9. 10.
Jansen L, de Niet A, Makowska Z, Dill MT, van Dort KA, Terpstra V, et al. An intrahepatic
transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B. Liver International. 2015. 11.
Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to
hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(17):6669-74. 12.
Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8(+) T cells
mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77(1):68-76. 13.
Rehermann B, Lau D, Hoofnagle JH, Chisari FV. Cytotoxic T lymphocyte responsiveness after
resolution of chronic hepatitis B virus infection. The Journal of clinical investigation. 1996;97(7):1655-65. 14.
Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, et al. Lamivudine treatment can
restore T cell responsiveness in chronic hepatitis B. The Journal of clinical investigation. 1998;102(5):968-75. 15.
Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I, Missale G, et al. Transient restoration of
anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. Journal of hepatology. 2003;39(4):595-605.
This article is protected by copyright. All rights reserved.
Accepted Article
Biopsy
Genetic signature
Personalized therapy
Received Date : 04-Feb-2015 Revised Date : 05-Feb-2015 Accepted Date : 06-Feb-2015 Article type
: Editorial
Towards personalized medicine in chronic HBV patients?
Author: Giovanni Sitia
Affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Correspondence should be addressed to: Giovanni Sitia, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy; Tel.: +39-02-2643-4956 FAX: +39-02-2643-6822.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12806 This article is protected by copyright. All rights reserved.
Accepted Article
Email: [email protected]
Abbreviations: HBV, Hepatitis B virus; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; NUCs, nucleos(t)ide analogues; Peg-IFN, pegylated interferon-α; cccDNA, covalently closed circular DNA; HBsAg, hepatitis B surface antigen; ALT, alanine aminotransferase. Conflict of interest: Nothing to declare.
Hepatitis B virus (HBV) is an hepatotropic DNA virus that infects only humans and chimpanzees causing acute and chronic liver disease. More than 350 million people worldwide have chronic hepatitis B (CHB), with almost 1 million deaths directly ascribable to the complication of chronic infection, e.g., liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) (1, 2). Since HBV does not cause direct hepatocellular damage, liver disease during CHB mainly results from repetitive cycles of immune mediated cell injury that are followed by secondary hepatocellular regeneration and liver repair processes in an endless and ineffective attempt to permanently eliminate the virus and restore anatomical and functional organ integrity (3). Overtime, chronic hepatocellular injury and its consequences put CHB patients at a great risk of developing liver fibrosis/cirrhosis and HCC (3).
Available antiviral therapies for CHB patients consist of nucleos(t)ide analogues (NUCs) - i.e. lamivudine, adefovir, entecavir, telbuvidine and tenofovir - which directly suppress HBV replication and/or pegylated interferon-α (Peg-IFN), which possesses both antiviral and immune regulatory functions (2).
This article is protected by copyright. All rights reserved.
Accepted Article
As potent inhibitors of the HBV polymerase, NUCs have been previously shown to reduce hepatocellular damage and to promote histological reversion of liver fibrosis/cirrhosis (4), although their effectiveness at containing the risk of HCC development remains questionable (5, 6). Unfortunately, a large fraction of chronically infected patients do not respond to NUCs with permanent elimination of HBV. Besides the difficulty of sustaining the costs of treatment, this is because of different reasons. First, all NUCs have an intrinsic limited efficacy as they do not target the HBV covalently closed circular DNA (cccDNA) - the template of viral transcription that resides episomally in the nucleus of the infected hepatocyte - which is thought to have a long half-life. As such, the likelihood of viral rebounds following treatment withdrawal remains quite high (7). Second, dose-limiting side effects and emergence of drug-resistant mutants, particularly in the case of first-generation NUCs, further limit the capacity of these molecules to completely eliminate the virus (8). In keeping with what mentioned above, NUC therapy rarely achieves loss of circulating hepatitis B surface antigen (HBsAg), which is a conceivable marker of cccDNA clearance and it is commonly considered the closest endpoint of sustained viral control (2). By contrast, therapy with Peg-IFN has the potential to induce antiviral and immunemediated functions that are curative of cccDNA and, therefore, it represents the only existing chance for sustained off-treatment responses. These apparent benefits are limited, however, to a minority of patients. In addition to associated side effects, factors that influence response rates to Peg-IFN therapy and currently guide clinical practice include age, relatively high alanine aminotransferase (ALT) levels, low viral load and infection with specific HBV genotypes (2, 9). Currently, there are no biomarkers able to predict the course of NUC or Peg-IFN therapy. Thus, unnecessary use of therapy in patients destined not to respond often occurs, resulting in overall unsatisfactory response rates.
Accepted Article
In this issue of Liver International, Jansen et al. identified a specific intrahepatic gene signature able to distinguish outcome of therapy (responders vs. non-responders) in CHB patients treated with adefovir and Peg-IFN (10). In particular, the authors utilized pre-treatment core-needle liver biopsies, to show that a group of genes related to the adaptive immune response - more specifically to antigen processing and presentation or leucocyte chemotaxis - are up-regulated in patients that ultimately responded to therapy (10). Conversely, this same pre-treatment intrahepatic signature appears not to be present in patients that failed to respond to therapy. The authors also realized that a variety of the up-regulated genes resemble the typical gene signature previously described in the liver of chimpanzees during the resolution phase of an acute HBV infection (11). To this regard, previous studies in acutely infected chimpanzees have shown that the innate immune response seems not to contribute significantly to the pathogenesis of liver disease or viral clearance (e.g., little or no induction of innate immune genes and/or IFN-responsive genes is observed in the liver of these animals before T cells enter the liver), while the adaptive immune response, especially the virus-specific effector CD8+ T cell response, contributes to both (e.g., a strong induction of not only IFN-responsive genes but also genes linked to antigen processing and presentation or leucocyte chemotaxis is observed in the chimp liver as T cells start entering the liver) (11). The importance of CD8+ T cells in the control of HBV is also highlighted by additional chimp studies in which the depletion of CD8+ T cells at the peak of HBV replication was shown to delay liver immunopathology and inhibit viral clearance (12). Based on these notions, it is evident that CD8+ T cell effector functions promote the resolution of HBV infection and that viral persistence results from the failure to induce or maintain these CD8+ T cell-dependent events.
In this context, the results of Jansen et al suggest that a pre-existing intrahepatic HBV-specific adaptive immune response, albeit dysfunctional and not sufficient to spontaneously clear the
This article is protected by copyright. All rights reserved.
Accepted Article
virus, is necessary for therapy-induced long-term control of HBV, in particular in the case of adefovir and Peg-IFN combination therapy. Future studies analyzing pre-treatment liver gene expression profiles are needed to understand whether similar or different results will be obtained in cohorts of patients receiving more potent NUCs with higher genetic barrier alone or in combination with Peg-IFN. Of note, the basic concept of pre-existing adaptive immune responses regulating treatment outcome fits with previous studies in which the relative extent of therapy responsiveness was measured against number and function of HBV-specific T cells circulating in blood before treatment initiation (13-15).
All in all, the results presented by Jansen et al. suggest a novel and personalized approach to
anti-viral therapy in CHB patients, where pre-treatment analyses of specific immunological gene signatures may help decisions to treatment. In this scenario, patients with immunological gene signatures associated with a sustained response to a particular therapy (should this be based on NUCs, Peg-IFN or both) might be directed towards specific therapeutic avenues with obvious benefit for the patient and health care systems at large. Clearly, much more work needs to be done in the trail designed by Jansen et al. This includes: i) the necessity of extending such analyses to large cohorts of patients that undergo different antiviral therapies; ii) the evaluation of analyzing genetically fine-needle aspiration biopsies instead of core-needle biopsies (thus rendering the sampling less risky and more attainable in the day-to-day clinical practice) and iii) the assessment of results coming from arrays composed of limited sets of predictive genes (thus rendering the genetic procedure more affordable). Patients, physicians and heath care providers await with hope.
Accepted Article
Acknowledgments I thank Luca G. Guidotti for critical reading of this manuscript. This work was partially supported by grant RF11.61 from the Italian Ministry of Health.
Figure Legend
Fig. 1 Towards personalized medicine in chronic HBV patients After liver biopsy and gene expression profiling, chronic HBV patients are stratified and directed to specific antiviral therapies. The figure was generated with images from Servier Medical Art (www.servier.com), licensed under the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/license/by/3.0/).
This article is protected by copyright. All rights reserved.
Accepted Article
References
1.
Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences.
N Engl J Med. 2004;350(11):1118-29. 2.
European Association For The Study Of The Liver. EASL clinical practice guidelines:
Management of chronic hepatitis B virus infection. Journal of hepatology. 2012;57(1):167-85. 3.
Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annual review
of pathology. 2006;1:23-61. 4.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis
during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75. 5.
Pellicelli AM, Vignally P, Messina V, Izzi A, Mazzoni E, Barlattani A, et al. Long term
nucleotide and nucleoside analogs treatment in chronic hepatitis B HBeAg negative genotype D patients and risk for hepatocellular carcinoma. Annals of hepatology. 2014;13(4):376-85.
6.
Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P. Risk of Hepatocellular
Carcinoma in Chronic Hepatitis B: Assessment and Modification With Current Antiviral Therapy. Journal of hepatology. 2015. 7.
Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus
infections: towards restoration of immune control of viral infection. Gut. 2012;61(12):1754-64. 8.
Zoulim F, Buti M, Lok AS. Antiviral-resistant hepatitis B virus: can we prevent this monster
from growing? Journal of viral hepatitis. 2007;14 Suppl 1:29-36.
Accepted Article
9.
Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, et al. Factors that
predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferonalfa. Gastroenterology. 2009;137(6):2002-9. 10.
Jansen L, de Niet A, Makowska Z, Dill MT, van Dort KA, Terpstra V, et al. An intrahepatic
transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B. Liver International. 2015. 11.
Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to
hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(17):6669-74. 12.
Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8(+) T cells
mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77(1):68-76. 13.
Rehermann B, Lau D, Hoofnagle JH, Chisari FV. Cytotoxic T lymphocyte responsiveness after
resolution of chronic hepatitis B virus infection. The Journal of clinical investigation. 1996;97(7):1655-65. 14.
Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, et al. Lamivudine treatment can
restore T cell responsiveness in chronic hepatitis B. The Journal of clinical investigation. 1998;102(5):968-75. 15.
Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I, Missale G, et al. Transient restoration of
anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. Journal of hepatology. 2003;39(4):595-605.
This article is protected by copyright. All rights reserved.
Accepted Article
Biopsy
Genetic signature
Personalized therapy
