學術著文｜莊輝：慢性HBV感染免疫耐受期應否治療？

慢性HBV病毒感染自體耐受期格外高血壓應該可不該給予化療是目前爲止國内外史學界争議較大、關注度很格外高的一個解決辦法。賓夕法尼亞州、西歐及亞太Guide一般不延攬對自體耐受期慢性HIV爲由化療，但有多位學者建議對HBV病毒感染自體耐受期格外高血壓透過抗原化療。

針對這一熱點極難解決辦法，《臨床腎髒膽病周報》附設“史學時評”欄目，并邀請莊輝教授撰文與大家一起談論，作爲開始，不是确定。本刊勇氣贊賞廣大讀者就此議題上百加入談論，來稿将陸續刊發。

今後，本刊将“史學時評”設爲一直一般來說欄目，以解決辦法爲導向，提倡史學正直、公平，百家時評，百花齊放，在秉持史學自由民主的知性中的探索道理，爲推動本學科史學時評盡可不有職責。

有約，全球慢性HBV病毒HIV近2.92億人，其中的自體耐受期格外高血壓近1.98億［1］。現狀慢性HBV病毒HIV近8600萬可有，其中的自體耐受期格外高血壓近3230萬［1］。

目前爲止賓夕法尼亞州［2］、西歐［3］和亞太［4］眼疾學就會發布新聞的慢性HIV（CHB）診治Guide（以下前身賓夕法尼亞州Guide、西歐Guide和亞太Guide）關于自體耐受期CHB（IT-CHB）格外高血壓的定義及化療的延攬異議不完全一緻：賓夕法尼亞州Guide［2］中的ALT短時間數值上限（ULN）成年爲30 U/L，未婚爲25 U/L；西歐和亞太Guide中的ALT ULN**皆爲40 U/L。關于IT-CHB定義，賓夕法尼亞州Guide：HBV DNA＞106 IU/ml，ALT短時間；西歐Guide：HBV DNA＞107 IU/ml，ALT持續短時間；亞太Guide：HBV DNA＞20 000 IU/ml，ALT 1~2×ULN。關于IT-CHB化療的延攬異議，賓夕法尼亞州和亞太Guide皆隻延攬對腎髒活體顯示中的度/重度上皮細胞（A3）或顯着潰瘍（F2）的IT-CHB格外高血壓化療；西歐Guide則延攬增大IT-CHB化療指征：即年歲＞30歲，或有腎髒腫瘤（HCC）/并發症的有，或有腎髒外表現的IT-CHB格外高血壓，即使ALT和腎髒活體短時間，也可以化療。

2020年5年末，Jeng等［5］在“理可不增大CHB化療指征”一文中的明确提出，對有稍微/方面性眼疾論據的灰區（即HBV DNA＜106 IU/ml）或年歲＞40歲的IT-CHB格外高血壓透過抗原化療，較賓夕法尼亞州Guide增大了化療指征。2020年9年末，中的國日本和長崎10名專家聯合發表關于啓動時CHB化療遠東專家異議［6］，延攬ALT ULN成年爲30 U/L，未婚爲19 U/L，對ALT≥1×ULN格外高血壓，延攬抗原化療。該專家異議增大了頗爲一部分IT-CHB格外高血壓的抗原化療。

賓夕法尼亞州、西歐和亞太Guide不延攬對IT-CHB化療的原因是：（1）IT-CHB是良性病症期，不起因并發症和HCC或起因率很低［7-12］；（2）IT-CHB格外高血壓的腎髒第三活體無或輕微上皮細胞和/或潰瘍［2,9,13-14］；（3）治果欠，大多起因HBeAg血清學變換或HBsAg遺忘［5,15-19］；可自發自體依靠達到HBeAg血清學變換［8,20-21］；（4）IT-CHB格外高血壓多爲青年人，對一直抗原化療依從性欠，易起因病原體性［12,22］。

2015年，Bertoletti等［23］對HBV病毒感染自體耐受期方法論明确提出抗議，視爲這是老方法論，依賴于自體學論據。2016年，Gastroenterology周報第三組織專家對“自體耐受期方法論”透過了談論［24-28］。Bertoletti等［23-25,28］視爲不可不稱作IT-CHB，建議改爲“格外高複制低上皮細胞期（HRLI）”，原因是：（1）在胎兒要到期已存在效可不和調節自體這樣的話；（2）男嬰和嬰兒可産生病原體抗原T胸腺這樣的話；（3）男嬰和嬰兒的自體系統本身并無毛病；（4）兒童在1歲内注射HIV接種有效地；（5）不同期HIV格外高血壓（還包括自體耐受期）皆有HBV抗原T胸腺這樣的話、HBV DNA緊密結合和了了腎髒增量，說明心肌梗塞起因要到就啓動時。但Milich［26］和Liaw等［27］視爲将IT-CHB易名爲HRLI的論據尚不充分。2017年西歐Guide首先将IT-CHB年末易名爲“HBeAg乙型腎髒炎慢性HBV病毒感染”。

自2018年以來，特别是2020年，多位學者［29-33］明确提出，可不對HBV自體耐受期格外高血壓化療，以增格外高其起因并發症和HCC的風險，原因如下。

Mason等［24］測定26可有慢性HBV病毒HIV，其中的9可有IT-CHB格外高血壓、10可有HBeAg乙型腎髒炎CHB格外高血壓、7可有HBeAg乙型腎髒炎CHB格外高血壓，辨認出IT-CHB格外高血壓與HBeAg乙型腎髒炎和乙型腎髒炎CHB格外高血壓一樣，也可測定到HBV DNA緊密結合、腎髒特異性、了了腎髒增量、HBV抗原T胸腺這樣的話以及腎髒損傷。Chu等［8］随訪240可有IT-CHB格外高血壓17年，并發症會有起因率爲12.6%。Chen等［34］随訪251可有IT-CHB格外高血壓13年，HCC會有起因率爲5.1%。Beasley等［35］前瞻性随訪22 707可有40~59歲中的國台灣成年，其中的15.2%爲HBsAg病毒病毒感染，平皆随訪3.3年，HBsAg病毒病毒感染的HCC發病（1158/10都來年）總體格外高于非病毒病毒感染（5/10都來年）。Sun等［36］歸納現狀161個病症受控點1990年—2014年的HCC發病資料辨認出，無論是大都市還是農村，成年和未婚HCC發病皆随年歲快速增長而顯着升格外高，特别是在30歲以後（由此可知1）。HCC的起因是一個一直發展緻病過程，說明要到在30歲以前HCC起因要到就啓動時［35］。

由此可知1 現狀1990年—2014年161個病症受控點城鄉**HCC年歲死亡者專率［36］

Kim等［37］歸納日本所私立大學三甲的醫院2000年—2013年病可有鏈表，其中的未能化療的IT-CHB格外高血壓413可有、核苷(硫酸)類似若無（NAs）化療的自體活動期CHB格外高血壓1497可有，%-，未能化療的IT-CHB格外高血壓10年會有HCC發病和死亡者/開腹起因率（共有12.7%和9.7%）總體格外高于化療的自體活動期CHB格外高血壓（共有6.1%和3.4%）（P數值共有0.001、0.001）。

既往雖有新聞報道［2,9,13-14］，IT-CHB格外高血壓的腎髒第三活體無或輕微上皮細胞和/或潰瘍，但近些年有多篇新聞報道［9,38-44］表明，28%~49%的IT-CHB格外高血壓有顯着的腎髒上皮細胞壞死和腎髒潰瘍（≥G2/S2）病理學改變（表1）。

既往曾新聞報道［5,15-19］，IT-CHB格外高血壓給予抗原治果較欠，大多起因HBeAg血清學變換或HBsAg遺忘。但近些年有多項史學研究［45-47］顯示，分析方法NAs化療IT-CHB格外高血壓，雖然HBeAg血清學變換或HBsAg遺忘率低，但增格外高血清HBV DNA素質效果總體。Chan等［45］用替諾福韋酯（TDF）或TDF/恩曲他濱（FTC）分别化療64可有和62可有IT-CHB格外高血壓，半數爲33歲，89%爲亞洲人，B和C子代占93%，99%爲HBeAg乙型腎髒炎，HBV DNA素質爲8.41 log10 IU/ml,化療至192就有，TDF第三組55%(35/64)、TDF/FTC第三組76%(47/62) 格外高血壓的HBV DNA素質降至＜69 IU/ml，與曲率半徑尤其有總體欠異（P=0.016）。Pan等［46］和Jourdain等［47］曾于在IT-CHB新生兒中的，籌劃TDF預防HBV診療傳播的格外高血壓史學研究，将IT-CHB新生兒随機可分化療第三組和依此第三組，Pan等［46］于孕30~32周至産婦4周，Jourdain等［47］于孕28周至産婦2周，分别給予各第三組新生兒TDF或口服，産婦時（即化療8~12周）測定所有新生兒HBV DNA，%-TDF第三組HBV DNA素質分别下降4.7 log IU/ml和4.0 log IU/ml，而口服第三組HBV DNA素質無下降，仍維持在曲率半徑素質。日本Chang等［48］籌劃了一項政府機構多中的心回顧性史學研究，歸納2006年1年末—2016年3年末日本8所大型的醫院共計484可有IT-CHB格外高血壓（HBeAg乙型腎髒炎、HBV DNA素質＞20 000 IU/ml，ALT素質＜40 U/L、無并發症），其中的87可有給予抗原化療，397可有未能給予抗原化療作爲依此，經傾向記扣除對歸納，10年間化療第三組會有HCC及并發症起因率總體最低依此第三組（P數值共有0.046、0.015）（由此可知2）。

由此可知2 日本多中的心IT-CHB格外高血壓抗原化療回顧性歸納HCC及并發症會有起因率［48］

HBV DNA素質是HCC起因的獨立生命危險因素，增格外高血清HBV DNA素質可總體增加HCC起因風險。Chen等［49］對基于社區1991年—1992年入第三組的3653可有（30~65歲）HBsAg乙型腎髒炎者前瞻性鏈表，平皆随訪11.4年，辨認出其會有HCC起因率與入第三組時HBV DNA素質有關，入第三組時HBV DNA素質＜300、300~9999、10 000~99 999、100 000~999 999和≥1 000 000 解碼/ml格外高血壓HCC會有起因率共有1.30%、1.37%、3.57%、12.17%和14.89%，随HBV DNA素質上升而總體升格外高。

各國Guide［2-4,50］指出，化療CHB的目的是：最大限度地一直抑制HBV複制，加重腎髒上皮細胞壞死及腎髒纖維第三組織發炎，延緩和增加腎髒功能衰竭、并發症惜代償、HCC和其他并發症的起因，提格外高格外高血壓貧困質量，延長其存活時間，而不僅僅是爲了個别HBV标志若無的變換或遺忘。因此，從增格外高并發症和HCC風險來看，NAs化療IT-CHB格外高血壓的效果是總體的。

（1）現有HIV口服抗病若無恩替卡韋（ETV）、TDF、富馬硫酸丙酚替諾福韋（TAF）一直化療安全性好、病原體性起因率低［51-59］：ETV 5年會有病原體性起因率僅爲1.2%［53］；TDF 8年未能辨認出病原體性［55］；TAF 3年無病原體性［58-59］。

（2）一直化療依從性欠，不能作爲不化療的原因，因CHB格外高血壓和其他慢性病症格外高血壓也即可一直化療，化療的依從性可通過健康教育等措施進一步提格外高［31,60-61］。

（3）化療實用性格外高。目前爲止HIV抗病若無的化療費最低受控費，且IT-CHB格外高血壓對受控依從性欠。據新聞報道［19，62］，近61%的HCC格外高血壓爲首次就診，說明這些格外高血壓既往未能給予受控。

（4）對IT-CHB格外高血壓抗原化療可增格外高HBV素質傳播和診療傳播，并可增加HIV歧視［46-47,63-64］。

（5）對IT-CHB格外高血壓化療可進一步提格外高HIV診斷率和化療率［30，32，65］，實現世界衛生第三組織明确提出的到2030年掃除HIV公共服務威脅的目标［66］。

鑒于（1） IT-CHB不是良性病症期；（2）對IT-CHB格外高血壓化療可增格外高并發症和HCC的起因；（3）一線用藥抗原戰鬥能力強，病原體性起因率低，一直化療安全有效地；（4）化療費最低受控費，實用性格外高；（5）可增格外高HBV素質傳播和診療傳播，增加HIV歧視；（6）可進一步提格外高HIV診斷率和化療率，實現世界衛生第三組織明确提出的到2030年掃除HIV公共威脅的目标。因此，可不增大對IT-CHB格外高血壓的化療。同時，可不籌劃對IT-CHB格外高血壓化療的史學研究，提供者格外多的循證醫學論據，如（1）回顧性前瞻性鏈表史學研究：尤其IT-CHB化療第三組、未能化療第三組和HBeAg乙型腎髒炎自體稍微HIV化療第三組會有并發症起因率、HCC發病、開腹率及發病；（2）前瞻性鏈表史學研究：尤其3第三組會有并發症起因率、HCC發病、開腹率及發病；（3）格外高血壓史學研究：尤其2第三組會有并發症起因率、HCC發病、開腹率及發病等。

參考文獻:

［1］Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study［J］. Lancet Gastroenterol Hepatol, 2018, 3(6): 383-403.

［2］TERRAULT NA, LOK A, MCMAHON BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance［J］. Hepatology, 2018, 67(4): 1560-1599.

［3］European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection［J］. J Hepatol, 2017, 67(2): 370-398.

［4］SARIN SK, KUMAR M, LAU GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update［J］. Hepatol Int, 2016, 10(1): 1-98.

［5］JENG WJ, LOK AS. Should Treatment indications for chronic hepatitis B be expanded?［J］. Clin Gastroenterol Hepatol, 2020. ［Epub ahead of print］

［6］KAO JH, HU TH, JIA J, et al. East Asia expert opinion on treatment initiation for chronic hepatitis B［J］. Aliment Pharmacol Ther, 2020, 52(10): 1540-1550.

［7］CORNBERG M, LOK AS, TERRAULT NA, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B-Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference［J］. J Hepatol, 2020, 72(3): 539-557.

［8］CHU CM, HUNG SJ, LIN J, et al. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels［J］. Am J Med, 2004, 116(12): 829-834.

［9］ANDREANI T, SERFATY L, MOHAND D, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: Histologic findings and outcome［J］. Clin Gastroenterol Hepatol, 2007, 5(5): 636-641.

［10］LEE HW, KIM SU, BAATARKHUU O, et al. Comparison between chronic hepatitis B patients with untreated immune-tolerant phase vs. those with virological response by antivirals［J］. Sci Rep, 2019, 9(1): 2508.

［11］LEE HA, LEE HW, KIM IH, et al. Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase［J］. Aliment Pharmacol Ther, 2020, 52(1): 196-204.

［12］LEE HW, KIM EH, LEE J, et al. Correction to: Natural history of untreated HBeAg-positive chronic HBV infection with persistently elevated HBV DNA but normal alanine aminotransferase［J］. Clin Transl Gastroenterol, 2020, 11(5): e00183.

［13］HUI CK, LEUNG N, YUEN ST, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase［J］. Hepatology, 2007, 46(2): 395-401.

［14］MCMAHON BJ. Epidemiology and natural history of hepatitis B［J］. Semin Liver Dis, 2005, 25(Suppl 1): 3-8.

［15］WU IC, LAI CL, HAN SH, et al. Efficacy of entecir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy-proven histological damage［J］. Hepatology, 2010, 51(4): 1185-1189.

［16］WONG VW, HUI AJ, WONG GL, et al. Four-year outcomes after cessation of tenofovir in immune-tolerant chronic hepatitis B patients［J］. J Clin Gastroenterol, 2018, 52(4): 347-352.

［17］ROSENTHAL P, LING SC, BELLE SH, et al. Combination of entecir/peginterferon alfa-2a in children with hepatitis B e antigen-positive immune tolerant chronic hepatitis B virus infection［J］. Hepatology, 2019, 69(6): 2326-2337.

［18］FELD JJ, TERRAULT NA, LIN HS, et al. Entecir and peginterferon alfa-2a in s with hepatitis B e antigen-positive immune-tolerant chronic hepatitis B virus infection［J］. Hepatology, 2019, 69(6): 2338-2348.

［19］LEE HW, CHAN HL. Unresolved issues of immune tolerance in chronic hepatitis B［J］. J Gastroenterol, 2020, 55(4): 383-389.

［20］WU JF, SU YR, CHEN CH, et al. Predictive effect of serial serum alanine aminotransferase levels on spontaneous HBeAg seroconversion in chronic genotype B and C HBV-infected children［J］. J Pediatr Gastroenterol Nutr, 2012, 54(1): 97-100.

［21］CHEN YC, CHU CM, LIAW YF. Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B［J］. Hepatology, 2010, 51(2): 435-444.

［22］DOLMAN GE, KOFFAS A, MASON WS, et al. Why, who and when to start treatment for chronic hepatitis B infection［J］. Curr Opin Virol, 2018, 30: 39-47.

［23］BERTOLETTI A, KENNEDY PT. The immune tolerant phase of chronic HBV infection: New perspectives on an old concept［J］. Cell Mol Immunol, 2015, 12(3): 258-263.

［24］MASON WS, GILL US, LITWIN S, et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant［J］. Gastroenterology, 2016, 151(5): 986-998.

［25］PROTZER U, KNOLLE P. “To Be or Not to Be”: Immune tolerance in chronic hepatitis B［J］. Gastroenterology, 2016, 151(5): 805-806.

［26］MILICH DR. The concept of immune tolerance in chronic hepatitis B virus infection is alive and well［J］. Gastroenterology, 2016, 151(5): 801-804.

［27］LIAW YF, CHU CM. Immune tolerance phase of chronic hepatitis B［J］. Gastroenterology, 2017, 152(5): 1245-1246.

［28］KENNEDY PTF, BERTOLETTI A, MASON WS. Reply to immune tolerance phase of chronic hepatitis B［J］. Gastroenterology, 2017, 152(5): 1246-1247.

［29］WONG GL. Management of chronic hepatitis B patients in immunetolerant phase: What latest guidelines recommend［J］. Clin Mol Hepatol, 2018, 24(2): 108-113.

［30］KLAIR JS, VANCURA J, MURALI AR. PRO: Patients with chronic hepatitis B in immune-tolerant phase should be treated［J］. Clin Liver Dis (Hoboken), 2020, 15(1): 21-24.

［31］HOWELL J, CHAN H, FELD JJ, et al. Closing the stable door after the horse has bolted: Should we be treating people with immune-tolerant chronic hepatitis B to prevent hepatocellular carcinoma?［J］. Gastroenterology, 2020, 158(8): 2028-2032.

［32］KOFFAS A, PETERSEN J, KENNEDY PT. Reasons to consider early treatment in chronic hepatitis B patients［J］. Antiviral Res, 2020, 177: 104783.

［33］KIM HL, KIM GA, PARK JA, et al. Cost-effectiveness of antiviral treatment in patients with immune-tolerant phase chronic hepatitis B［J］. Gut, 2020. ［Epub ahead of print］

［34］CHEN CF, LEE WC, YANG HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma［J］. Gastroenterology, 2011, 141(4): 1240-1248.

［35］BEASLEY RP, HWANG LY, LIN CC, et al. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan［J］. Lancet, 1981, 2(8256): 1129-1133.

［36］SUN Y, WANG Y, LI M, et al. Long-term trends of liver cancer mortality by gender in urban and rural areas in China: An age-period-cohort ysis［J］. BMJ Open, 2018, 8(2): e020490.

［37］KIM GA, LIM YS, HAN S, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B［J］. Gut, 2018, 67(5): 945-952.

［38］WANG C, DEUBNER H, SHUHART M, et al. High prevalence of significant fibrosis in patients with immunotolerance to chronic hepatitis B infection［J］. Hepatology, 2005, 42(Suppl 1): a573.

［39］LAI M, HYATT BJ, NASSER I, et al. The clinical significance of persistently normal ALT in chronic hepatitis B infection［J］. J Hepatol, 2007, 47(6): 760-767.

［40］PARK JY, PARK YN, KIM DY, et al. High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels［J］. J Viral Hepat, 2008, 15(8): 615-621.

［41］KUMAR M, SARIN SK, HISSAR S, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT［J］. Gastroenterology, 2008, 134(5): 1376-1384.

［42］NGUYEN MH, GARCIA RT, TRINH HN, et al. Histological disease in Asian-Americans with chronic hepatitis B, high hepatitis B virus DNA, and normal alanine aminotransferase levels［J］. Am J Gastroenterol, 2009, 104(9): 2206-2213.

［43］SETO WK, LAI CL, IP PP, et al. A large population histology study showing the lack of association between ALT elevation and significant fibrosis in chronic hepatitis B［J］. PLoS One, 2012, 7(2): e32622.

［44］LIAO B, WANG Z, LIN S, et al. Significant fibrosis is not rare in Chinese chronic hepatitis B patients with persistent normal ALT［J］. PLoS One, 2013, 8(10): e78672.

［45］CHAN HL, CHAN CK, HUI AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA［J］. Gastroenterology, 2014, 146(5): 1240-1248.

［46］PAN CQ, DUAN Z, DAI E, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load［J］. N Engl J Med, 2016, 374(24): 2324-2334.

［47］JOURDAIN G, NGO-GIANG-HUONG N, HARRISON L, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B［J］. N Engl J Med, 2018, 378(10): 911-923.

［48］CHANG Y, CHOE WH, SINN DH, et al. Nucleos(t)ide ogue treatment for patients with hepatitis B virus (HBV) e antigen-positive chronic HBV genotype C infection: A nationwide, multicenter, retrospective study［J］. J Infect Dis, 2017, 216(11): 1407-1414.

［49］CHEN CJ, YANG HI, SU J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level［J］. JAMA, 2006, 295(1): 65-73.

［50］Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)［J］. J Clin Hepatol, 2019, 35(12): 2648-2669. (in Chinese)

中的華醫學就會病毒感染病文憑就會, 中的華醫學就會眼疾文憑就會. 慢性HIV防治Guide(2019年版)［J］. 臨床腎髒膽病周報, 2019, 35(12): 2648-2669.

［51］LAMPERTICO P, CHAN HL, JANSSEN HL, et al. Review article: Long-term safety of nucleoside and nucleotide ogues in HBV-monoinfected patients［J］. Aliment Pharmacol Ther, 2016, 44(1): 16-34.

［52］de VRIES-SLUIJS TE, REIJNDERS JG, HANSEN BE, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus［J］. Gastroenterology, 2010, 139(6): 1934-1941.

［53］TENNEY DJ, ROSE RE, BALDICK CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecir in nucleoside-nave patients is rare through 5 years of therapy［J］. Hepatology, 2009, 49(5): 1503-1514.

［54］KITRINOS KM, CORSA A, LIU Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B［J］. Hepatology, 2014, 59(2): 434-442.

［55］LIU Y, CORSA AC, BUTI M, et al. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment［J］. J Viral Hepat, 2017, 24(1): 68-74.

［56］LIU Y, MILLER MD, KITRINOS KM. Tenofovir alafenamide demonstrates broad cross-genotype activity against wild-type HBV clinical isolates and maintains susceptibility to drug-resistant HBV isolates invitro［J］. Antiviral Res, 2017, 139: 25-31.

［57］AGARWAL K, BRUNETTO M, SETO WK, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection［J］. J Hepatol, 2018, 68(4): 672-681.

［58］CATHCART AL, CHAN HL, BHARDWAJ N, et al. No resistance to tenofovir alafenamide detected through 96 weeks of treatment in patients with chronic hepatitis B infection［J］. Antimicrob Agents Chemother, 2018, 62(10): e01064-18.

［59］CHAN HLY, MARCELLIN P, PAN CQ, et al. No resistance to tenofovir alafenamide detected through 144 weeks of treatment in patients with chronic hepatitis B［J］. Hepatology, 2018, 68(Suppl 1): 231A.

［60］COOKE GS, ANDRIEUX-MEYER I, APPLEGATE TL, et al. Accelerating the elimination of viral hepatitis: A Lancet Gastroenterology & Hepatology Commission［J］. Lancet Gastroenterol Hepatol, 2019, 4(2): 135-184.

［61］SCHREDER SE, PEDRANA A, SCOTT N, et al. Innovative strategies for the elimination of viral hepatitis at a national level: A country case series［J］. Liver Int, 2019, 39(10): 1818-1836.

［62］ENRIQUEZ AD, CAMPBELL MS, REDDY KR. Cost-effectiveness of suppressing hepatitis B virus DNA in immune tolerant patients to prevent hepatocellular carcinoma and cirrhosis［J］. Aliment Pharmacol Ther, 2007, 26(3): 383-391.

［63］FREW PM, ALHANTI B, VO-GREEN L, et al. Multilevel factors influencing hepatitis B screening and vaccination among Vietnamese Americans in Atlanta, Georgia［J］. Yale J Biol Med, 2014, 87(4): 455-471.

［64］VEDIO A, LIU E, LEE A, et al. Improving access to health care for chronic hepatitis B among migrant Chinese populations: A systematic mixed methods review of barriers and enablers［J］. J Viral Hepat, 2017, 24(7): 526-540.

［65］KENNEDY P, LITWIN S, DOLMAN GE, et al. Immune tolerant chronic hepatitis B: The unrecognized risks［J］. Viruses, 2017, 9(5): 96.

［66］World Health Organization. Global Hepatitis Report［R/OL］. Geneva: WHO, 2017. 10.11.19.

本文編輯：葛俊

公衆号編輯：邢翔宇