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Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e‐antigen seroconversion
Hyperexpression of the programmed death 1 (PD‐1) molecule is a hallmark of exhausted T‐cells, having a negative impact on T‐cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)–positive patients undergoing treatment with direct antivirals (telbivudine or lamivudin...
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| Published in: | Hepatology (Baltimore, Md.) Md.), 2008-09, Vol.48 (3), p.759-769 |
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| cited_by | cdi_FETCH-LOGICAL-c4549-ecce45d0467e5eeae460a8332720543afffdb17f0601e9971aed87633661e313 |
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| container_title | Hepatology (Baltimore, Md.) |
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| creator | Evans, Alexander Riva, Antonio Cooksley, Helen Phillips, Sandra Puranik, Smrithi Nathwani, Amit Brett, Sara Chokshi, Shilpa Naoumov, Nikolai V. |
| description | Hyperexpression of the programmed death 1 (PD‐1) molecule is a hallmark of exhausted T‐cells, having a negative impact on T‐cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)–positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment‐induced viremia reduction and HBeAg seroconversion with respect to PD‐1 levels and T‐cell reactivity. PD‐1 expression was assessed by (1) flow cytometry and (2) quantitative real‐time polymerase chain reaction; hepatitis B virus (HBV)–specific CD8+ T‐cells were quantitated by pentamer staining; T‐cell reactivity to HBV antigens was determined by interferon gamma (IFNγ) and interleukin 10 (IL‐10) enzyme‐linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD‐1 expression correlated closely with viremia levels. On therapy, PD‐1 decreased significantly on total CD8+ T‐cells, HBV‐specific CD8+ T‐cells, and CD3+/CD8− T‐cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD‐1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD‐1 decrease with a 50% reduction in the frequency of PD‐1+/CD8+ T‐cells, which was not observed in patients remaining HBeAg‐positive. The decrease in PD‐1 expression was associated with increased frequencies of IFNγ‐producing T‐cells and decreased frequencies of IL‐10 producing T‐cells. At baseline, PD‐1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD‐1 expression and HBcAg‐specific effector phenotypes. Conclusion: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD‐1 expression and resulting T‐cell impairment. Treatment‐induced suppression of HBV replication reduces PD‐1 expression; however, additional immunotherapeutic interventions are needed for restoration of T‐cell functions. (HEPATOLOGY 2008.) |
| doi_str_mv | 10.1002/hep.22419 |
| format | article |
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We studied longitudinally 18 hepatitis B e antigen (HBeAg)–positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment‐induced viremia reduction and HBeAg seroconversion with respect to PD‐1 levels and T‐cell reactivity. PD‐1 expression was assessed by (1) flow cytometry and (2) quantitative real‐time polymerase chain reaction; hepatitis B virus (HBV)–specific CD8+ T‐cells were quantitated by pentamer staining; T‐cell reactivity to HBV antigens was determined by interferon gamma (IFNγ) and interleukin 10 (IL‐10) enzyme‐linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD‐1 expression correlated closely with viremia levels. On therapy, PD‐1 decreased significantly on total CD8+ T‐cells, HBV‐specific CD8+ T‐cells, and CD3+/CD8− T‐cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD‐1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD‐1 decrease with a 50% reduction in the frequency of PD‐1+/CD8+ T‐cells, which was not observed in patients remaining HBeAg‐positive. The decrease in PD‐1 expression was associated with increased frequencies of IFNγ‐producing T‐cells and decreased frequencies of IL‐10 producing T‐cells. At baseline, PD‐1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD‐1 expression and HBcAg‐specific effector phenotypes. Conclusion: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD‐1 expression and resulting T‐cell impairment. Treatment‐induced suppression of HBV replication reduces PD‐1 expression; however, additional immunotherapeutic interventions are needed for restoration of T‐cell functions. (HEPATOLOGY 2008.)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.22419</identifier><identifier>PMID: 18697210</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adult ; Alanine Transaminase - blood ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antigens, CD - metabolism ; Antiviral agents ; Antiviral Agents - therapeutic use ; Apoptosis Regulatory Proteins - metabolism ; Biological and medical sciences ; Biopsy ; CD8-Positive T-Lymphocytes - metabolism ; CD8-Positive T-Lymphocytes - pathology ; DNA, Viral - blood ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatitis B e Antigens - blood ; Hepatitis B virus - genetics ; Hepatitis B virus - physiology ; Hepatitis B, Chronic - drug therapy ; Hepatitis B, Chronic - immunology ; Hepatitis B, Chronic - metabolism ; Human viral diseases ; Humans ; Infectious diseases ; Interferon-gamma - metabolism ; Interleukin-10 - metabolism ; Lamivudine - therapeutic use ; Liver - metabolism ; Liver - pathology ; Liver - virology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Longitudinal Studies ; Male ; Medical sciences ; Middle Aged ; Nucleosides - therapeutic use ; Pharmacology. Drug treatments ; Programmed Cell Death 1 Receptor ; Pyrimidinones - therapeutic use ; Thymidine - analogs & derivatives ; Treatment Outcome ; Viral diseases ; Viral hepatitis ; Viral Load ; Viremia</subject><ispartof>Hepatology (Baltimore, Md.), 2008-09, Vol.48 (3), p.759-769</ispartof><rights>Copyright © 2008 American Association for the Study of Liver Diseases</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4549-ecce45d0467e5eeae460a8332720543afffdb17f0601e9971aed87633661e313</citedby><cites>FETCH-LOGICAL-c4549-ecce45d0467e5eeae460a8332720543afffdb17f0601e9971aed87633661e313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.22419$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.22419$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20613383$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18697210$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Evans, Alexander</creatorcontrib><creatorcontrib>Riva, Antonio</creatorcontrib><creatorcontrib>Cooksley, Helen</creatorcontrib><creatorcontrib>Phillips, Sandra</creatorcontrib><creatorcontrib>Puranik, Smrithi</creatorcontrib><creatorcontrib>Nathwani, Amit</creatorcontrib><creatorcontrib>Brett, Sara</creatorcontrib><creatorcontrib>Chokshi, Shilpa</creatorcontrib><creatorcontrib>Naoumov, Nikolai V.</creatorcontrib><title>Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e‐antigen seroconversion</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Hyperexpression of the programmed death 1 (PD‐1) molecule is a hallmark of exhausted T‐cells, having a negative impact on T‐cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)–positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment‐induced viremia reduction and HBeAg seroconversion with respect to PD‐1 levels and T‐cell reactivity. PD‐1 expression was assessed by (1) flow cytometry and (2) quantitative real‐time polymerase chain reaction; hepatitis B virus (HBV)–specific CD8+ T‐cells were quantitated by pentamer staining; T‐cell reactivity to HBV antigens was determined by interferon gamma (IFNγ) and interleukin 10 (IL‐10) enzyme‐linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD‐1 expression correlated closely with viremia levels. On therapy, PD‐1 decreased significantly on total CD8+ T‐cells, HBV‐specific CD8+ T‐cells, and CD3+/CD8− T‐cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD‐1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD‐1 decrease with a 50% reduction in the frequency of PD‐1+/CD8+ T‐cells, which was not observed in patients remaining HBeAg‐positive. The decrease in PD‐1 expression was associated with increased frequencies of IFNγ‐producing T‐cells and decreased frequencies of IL‐10 producing T‐cells. At baseline, PD‐1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD‐1 expression and HBcAg‐specific effector phenotypes. Conclusion: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD‐1 expression and resulting T‐cell impairment. Treatment‐induced suppression of HBV replication reduces PD‐1 expression; however, additional immunotherapeutic interventions are needed for restoration of T‐cell functions. (HEPATOLOGY 2008.)</description><subject>Adult</subject><subject>Alanine Transaminase - blood</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antigens, CD - metabolism</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biopsy</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>CD8-Positive T-Lymphocytes - pathology</subject><subject>DNA, Viral - blood</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatitis B e Antigens - blood</subject><subject>Hepatitis B virus - genetics</subject><subject>Hepatitis B virus - physiology</subject><subject>Hepatitis B, Chronic - drug therapy</subject><subject>Hepatitis B, Chronic - immunology</subject><subject>Hepatitis B, Chronic - metabolism</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin-10 - metabolism</subject><subject>Lamivudine - therapeutic use</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver - virology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Longitudinal Studies</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Nucleosides - therapeutic use</subject><subject>Pharmacology. Drug treatments</subject><subject>Programmed Cell Death 1 Receptor</subject><subject>Pyrimidinones - therapeutic use</subject><subject>Thymidine - analogs & derivatives</subject><subject>Treatment Outcome</subject><subject>Viral diseases</subject><subject>Viral hepatitis</subject><subject>Viral Load</subject><subject>Viremia</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNp1kM9O3DAQh60KVLYLB14A-QJSD4Hxn9jr3gBBQUIqB-6RcSa7Romd2llabvAGfcY-CVl2Vbj0NNLMp99P8xGyz-CYAfCTBfbHnEtmPpEJK7kuhChhi0yAaygME2aHfMn5AQCM5LPPZIfNlNGcwYS83KY4T7brsKY12mFBGcXffcKcfQy0XiYf5tSGwT_6ZFs6pBHqMAw0NtQtUgze0bHfDn7wmZ59o9ddb93b-cOa4t_nP6uUOQaaMUUXwyOmVccu2W5sm3FvM6fk7vLi7vyquPnx_fr89KZwspSmQOdQljVIpbFEtCgV2JkQXHMopbBN09T3TDeggKExmlmsZ1oJoRRDwcSUHK1j-xR_LjEPVeezw7a1AeMyV8pIw7XQI_h1DboUc07YVH3ynU1PFYNqpbsa_6redI_swSZ0eT8afCc3fkfgcAPY7GzbJBucz_84DooJMX4xJSdr7pdv8en_jdXVxe26-hXXKJkx</recordid><startdate>200809</startdate><enddate>200809</enddate><creator>Evans, Alexander</creator><creator>Riva, Antonio</creator><creator>Cooksley, Helen</creator><creator>Phillips, Sandra</creator><creator>Puranik, Smrithi</creator><creator>Nathwani, Amit</creator><creator>Brett, Sara</creator><creator>Chokshi, Shilpa</creator><creator>Naoumov, Nikolai V.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200809</creationdate><title>Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e‐antigen seroconversion</title><author>Evans, Alexander ; Riva, Antonio ; Cooksley, Helen ; Phillips, Sandra ; Puranik, Smrithi ; Nathwani, Amit ; Brett, Sara ; Chokshi, Shilpa ; Naoumov, Nikolai V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4549-ecce45d0467e5eeae460a8332720543afffdb17f0601e9971aed87633661e313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>Alanine Transaminase - blood</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antigens, CD - metabolism</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biopsy</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>CD8-Positive T-Lymphocytes - pathology</topic><topic>DNA, Viral - blood</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Hepatitis B e Antigens - blood</topic><topic>Hepatitis B virus - genetics</topic><topic>Hepatitis B virus - physiology</topic><topic>Hepatitis B, Chronic - drug therapy</topic><topic>Hepatitis B, Chronic - immunology</topic><topic>Hepatitis B, Chronic - metabolism</topic><topic>Human viral diseases</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin-10 - metabolism</topic><topic>Lamivudine - therapeutic use</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver - virology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Longitudinal Studies</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Nucleosides - therapeutic use</topic><topic>Pharmacology. Drug treatments</topic><topic>Programmed Cell Death 1 Receptor</topic><topic>Pyrimidinones - therapeutic use</topic><topic>Thymidine - analogs & derivatives</topic><topic>Treatment Outcome</topic><topic>Viral diseases</topic><topic>Viral hepatitis</topic><topic>Viral Load</topic><topic>Viremia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Evans, Alexander</creatorcontrib><creatorcontrib>Riva, Antonio</creatorcontrib><creatorcontrib>Cooksley, Helen</creatorcontrib><creatorcontrib>Phillips, Sandra</creatorcontrib><creatorcontrib>Puranik, Smrithi</creatorcontrib><creatorcontrib>Nathwani, Amit</creatorcontrib><creatorcontrib>Brett, Sara</creatorcontrib><creatorcontrib>Chokshi, Shilpa</creatorcontrib><creatorcontrib>Naoumov, Nikolai V.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Evans, Alexander</au><au>Riva, Antonio</au><au>Cooksley, Helen</au><au>Phillips, Sandra</au><au>Puranik, Smrithi</au><au>Nathwani, Amit</au><au>Brett, Sara</au><au>Chokshi, Shilpa</au><au>Naoumov, Nikolai V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e‐antigen seroconversion</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2008-09</date><risdate>2008</risdate><volume>48</volume><issue>3</issue><spage>759</spage><epage>769</epage><pages>759-769</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><notes>These authors contributed equally to this study.</notes><notes>Potential conflict of interest: Dr. Naoumov received grants from Idenix Pharmaceuticals.</notes><notes>fax: +44‐20‐7380‐0405</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Hyperexpression of the programmed death 1 (PD‐1) molecule is a hallmark of exhausted T‐cells, having a negative impact on T‐cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)–positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment‐induced viremia reduction and HBeAg seroconversion with respect to PD‐1 levels and T‐cell reactivity. PD‐1 expression was assessed by (1) flow cytometry and (2) quantitative real‐time polymerase chain reaction; hepatitis B virus (HBV)–specific CD8+ T‐cells were quantitated by pentamer staining; T‐cell reactivity to HBV antigens was determined by interferon gamma (IFNγ) and interleukin 10 (IL‐10) enzyme‐linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD‐1 expression correlated closely with viremia levels. On therapy, PD‐1 decreased significantly on total CD8+ T‐cells, HBV‐specific CD8+ T‐cells, and CD3+/CD8− T‐cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD‐1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD‐1 decrease with a 50% reduction in the frequency of PD‐1+/CD8+ T‐cells, which was not observed in patients remaining HBeAg‐positive. The decrease in PD‐1 expression was associated with increased frequencies of IFNγ‐producing T‐cells and decreased frequencies of IL‐10 producing T‐cells. At baseline, PD‐1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD‐1 expression and HBcAg‐specific effector phenotypes. Conclusion: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD‐1 expression and resulting T‐cell impairment. Treatment‐induced suppression of HBV replication reduces PD‐1 expression; however, additional immunotherapeutic interventions are needed for restoration of T‐cell functions. (HEPATOLOGY 2008.)</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>18697210</pmid><doi>10.1002/hep.22419</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Hepatology (Baltimore, Md.), 2008-09, Vol.48 (3), p.759-769 |
| issn | 0270-9139 1527-3350 |
| language | eng |
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| source | Wiley-Blackwell Journals |
| subjects | Adult Alanine Transaminase - blood Antibiotics. Antiinfectious agents. Antiparasitic agents Antigens, CD - metabolism Antiviral agents Antiviral Agents - therapeutic use Apoptosis Regulatory Proteins - metabolism Biological and medical sciences Biopsy CD8-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - pathology DNA, Viral - blood Female Gastroenterology. Liver. Pancreas. Abdomen Hepatitis B e Antigens - blood Hepatitis B virus - genetics Hepatitis B virus - physiology Hepatitis B, Chronic - drug therapy Hepatitis B, Chronic - immunology Hepatitis B, Chronic - metabolism Human viral diseases Humans Infectious diseases Interferon-gamma - metabolism Interleukin-10 - metabolism Lamivudine - therapeutic use Liver - metabolism Liver - pathology Liver - virology Liver. Biliary tract. Portal circulation. Exocrine pancreas Longitudinal Studies Male Medical sciences Middle Aged Nucleosides - therapeutic use Pharmacology. Drug treatments Programmed Cell Death 1 Receptor Pyrimidinones - therapeutic use Thymidine - analogs & derivatives Treatment Outcome Viral diseases Viral hepatitis Viral Load Viremia |
| title | Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e‐antigen seroconversion |
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