恩替卡韦与替诺福韦酯抗病毒治疗降低慢性乙型肝炎患者肝细胞癌发生风险的差异——一项韩国回顾性研究引发的思考
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摘要
近期,韩国学者Choi等在《JAMA Oncology》杂志上发表了一项真实世界研究,结果显示在降低慢性乙型肝炎(CHB)患者肝细胞癌发生风险方面,恩替卡韦治疗组与替诺福韦酯治疗组存在明显差异。这一结果与当前CHB抗病毒治疗领域的主流观点不尽相同,引起了学术界强烈讨论。该杂志同步发表的编辑述评中指出,该研究具有一定的临床意义,但仍存在诸多混杂因素有待进一步研究阐明,不应据此更改CHB患者的抗病毒治疗方案。以该研究为切入点,分析和探讨CHB患者接受长期核苷(酸)类药物抗病毒治疗的肝细胞癌发生风险受哪些关键因素影响。
Recently,Choi et al. published a real-world study in JAMA Oncology,which showed that there was a significant difference between the entecavir group and the tenofovir disoproxil fumarate group in reducing the risk of hepatocellular carcinoma( HCC) in chronic hepatitis B( CHB) patients. This result is inconsistent with the common point of view in antiviral therapy for CHB and has aroused a heated discussion in the academic world. The editorial simultaneously published in JAMA Oncology pointed out that the study by Choi et al. has certain clinical significance,but there are still many confounding factors which need to be further clarified,and therefore,the regimen of antiviral therapy for CHB patients cannot be changed based on this result. With reference to this result,this article analyzes the key influencing factors for the risk of HCC in CHB patients receiving long-term antiviral therapy with NAs.
Recently,Choi et al. published a real-world study in JAMA Oncology,which showed that there was a significant difference between the entecavir group and the tenofovir disoproxil fumarate group in reducing the risk of hepatocellular carcinoma( HCC) in chronic hepatitis B( CHB) patients. This result is inconsistent with the common point of view in antiviral therapy for CHB and has aroused a heated discussion in the academic world. The editorial simultaneously published in JAMA Oncology pointed out that the study by Choi et al. has certain clinical significance,but there are still many confounding factors which need to be further clarified,and therefore,the regimen of antiviral therapy for CHB patients cannot be changed based on this result. With reference to this result,this article analyzes the key influencing factors for the risk of HCC in CHB patients receiving long-term antiviral therapy with NAs.
引文
[1]CHOI J,KIM HJ,LEE J,et al. Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B:A korean nationwide cohort study[J]. JAMA Oncol,2018,5(1):30-36.
[2]FLEMMING JA,TERRAULT NA. Tenofovir vs entecavir for hepatocellular carcinoma prevention in patients with chronic hepatitis B:One of these things is not like the other[J]. JAMA Oncol,2018,5(1):17-18.
[3]CHIEN J,LIU J,LEE MH,et al. Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis[J]. J Gastroenterol Hepatol,2016,31(12):1971-1977.
[4]IDILMAN R,GUNSAR F,KORUK M,et al. Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naive chronic hepatitis B patients in the real-world setting[J]. J Viral Hepat,2015,22(5):504-510.
[5]HAN Y,ZENG A,LIAO H,et al. The efficacy and safety comparison between tenofovir and entecavir in treatment of chronic hepatitis B and HBV related cirrhosis:A systematic review and Meta-analysis[J]. Int Immunopharmacol,2017,42:168-175.
[6]SATO A,OHTSUKI M,HATA M,et al. Antitumor activity of IFN-lambda in murine tumor models[J]. J Immunol,2006,176(12):7686-7694.
[7]LI K,LIU H,GUO T. Th17/Treg imbalance is an indicator of liver cirrhosis process and a risk factor for HCC occurrence in HBV patients[J]. Clin Res Hepatol Gastroenterol,2017,41(4):399-407.
[8]CLIFFORD RJ,ZHANG J,MEERZAMAN DM,et al. Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma[J]. Hepatology,2010,52(6):2034-2043.
[9]CHEN VL,LE AK,PODLAHA O,et al. Soluble intercellular adhesion molecule-1 is associated with hepatocellular carcinoma risk:Multiplex analysis of serum markers[J]. Sci Rep,2017,7(1):11169.
[10]ZEKRI AN,EL DEEB S,BAHNASSY AA,et al. Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions[J]. World J Gastroenterol,2018,24(11):1228-1238.
[11]ZAMOR PJ,DELEMOS AS,RUSSO MW. Viral hepatitis and hepatocellular carcinoma:Etiology and management[J]. J Gastrointest Oncol,2017,8(2):229-242.
[12]TAN A,GAO Y,YAO Z,et al. Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population[J]. Tumour Biol,2016,37(5):6343-6348.
[13]SHIN JW,JUNG SW,LEE SB,et al. Medication nonadherence increases hepatocellular carcinoma,cirrhotic complications,and mortality in chronic hepatitis B patients treated with entecavir[J]. Am J Gastroenterol,2018,113(7):998-1008.
[14]CHOI MS,SINN DH,KIM SA,et al. The clinical and laboratory characteristics of patients with chronic hepatitis B using current or past antiviral therapy in Korea:A multi-center,nation-wide,cross-sectional epidemiologic study[J]. Gut Liver,2012,6(2):241-248.
[15]ZHANG W,WANG X,WANG Y,et al. Effective viral suppression is necessary to reduce hepatocellular carcinoma development in cirrhotic patients with chronic hepatitis B:Results of a10-year follow up[J]. Medicine(Baltimore),2017,96(44):e8454.
[16]WU IT,HU TH,HUNG CH,et al. Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-na6ve chronic hepatitis B patients with high viremia:A retrospective cohort study[J]Clin Microbiol Infect,2017,23(7):464-469.
[17]HOU JL,ZHAO W,LEE CH,et al. Prospective,randomized safety assessment of long-term therapy with entecavir or other agents in patients with chronic HBV infection[R]. AASLD Annual Meeting,2017.
[2]FLEMMING JA,TERRAULT NA. Tenofovir vs entecavir for hepatocellular carcinoma prevention in patients with chronic hepatitis B:One of these things is not like the other[J]. JAMA Oncol,2018,5(1):17-18.
[3]CHIEN J,LIU J,LEE MH,et al. Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis[J]. J Gastroenterol Hepatol,2016,31(12):1971-1977.
[4]IDILMAN R,GUNSAR F,KORUK M,et al. Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naive chronic hepatitis B patients in the real-world setting[J]. J Viral Hepat,2015,22(5):504-510.
[5]HAN Y,ZENG A,LIAO H,et al. The efficacy and safety comparison between tenofovir and entecavir in treatment of chronic hepatitis B and HBV related cirrhosis:A systematic review and Meta-analysis[J]. Int Immunopharmacol,2017,42:168-175.
[6]SATO A,OHTSUKI M,HATA M,et al. Antitumor activity of IFN-lambda in murine tumor models[J]. J Immunol,2006,176(12):7686-7694.
[7]LI K,LIU H,GUO T. Th17/Treg imbalance is an indicator of liver cirrhosis process and a risk factor for HCC occurrence in HBV patients[J]. Clin Res Hepatol Gastroenterol,2017,41(4):399-407.
[8]CLIFFORD RJ,ZHANG J,MEERZAMAN DM,et al. Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma[J]. Hepatology,2010,52(6):2034-2043.
[9]CHEN VL,LE AK,PODLAHA O,et al. Soluble intercellular adhesion molecule-1 is associated with hepatocellular carcinoma risk:Multiplex analysis of serum markers[J]. Sci Rep,2017,7(1):11169.
[10]ZEKRI AN,EL DEEB S,BAHNASSY AA,et al. Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions[J]. World J Gastroenterol,2018,24(11):1228-1238.
[11]ZAMOR PJ,DELEMOS AS,RUSSO MW. Viral hepatitis and hepatocellular carcinoma:Etiology and management[J]. J Gastrointest Oncol,2017,8(2):229-242.
[12]TAN A,GAO Y,YAO Z,et al. Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population[J]. Tumour Biol,2016,37(5):6343-6348.
[13]SHIN JW,JUNG SW,LEE SB,et al. Medication nonadherence increases hepatocellular carcinoma,cirrhotic complications,and mortality in chronic hepatitis B patients treated with entecavir[J]. Am J Gastroenterol,2018,113(7):998-1008.
[14]CHOI MS,SINN DH,KIM SA,et al. The clinical and laboratory characteristics of patients with chronic hepatitis B using current or past antiviral therapy in Korea:A multi-center,nation-wide,cross-sectional epidemiologic study[J]. Gut Liver,2012,6(2):241-248.
[15]ZHANG W,WANG X,WANG Y,et al. Effective viral suppression is necessary to reduce hepatocellular carcinoma development in cirrhotic patients with chronic hepatitis B:Results of a10-year follow up[J]. Medicine(Baltimore),2017,96(44):e8454.
[16]WU IT,HU TH,HUNG CH,et al. Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-na6ve chronic hepatitis B patients with high viremia:A retrospective cohort study[J]Clin Microbiol Infect,2017,23(7):464-469.
[17]HOU JL,ZHAO W,LEE CH,et al. Prospective,randomized safety assessment of long-term therapy with entecavir or other agents in patients with chronic HBV infection[R]. AASLD Annual Meeting,2017.