学术著文｜庄辉：慢性HBV感染免疫耐受期应否治疗？

慢性HBV病毒感染自体耐受期格外高血压应该可不该给予化疗是目前为止国内外史学界争议较大、关注度很格外高的一个解决办法。宾夕法尼亚州、西欧及亚太Guide一般不延揽对自体耐受期慢性HIV为由化疗，但有多位学者建议对HBV病毒感染自体耐受期格外高血压透过抗原化疗。

针对这一热点极难解决办法，《临床肾脏胆病周报》附设“史学时评”栏目，并邀请庄辉教授撰文与大家一起谈论，作为开始，不是确定。本刊勇气赞赏广大读者就此议题上百加入谈论，来稿将陆续刊发。

今后，本刊将“史学时评”设为一直一般来说栏目，以解决办法为导向，提倡史学正直、公平，百家时评，百花齐放，在秉持史学自由民主的知性中的探索道理，为推动本学科史学时评尽可不有职责。

有约，全球慢性HBV病毒HIV近2.92亿人，其中的自体耐受期格外高血压近1.98亿［1］。现状慢性HBV病毒HIV近8600万可有，其中的自体耐受期格外高血压近3230万［1］。

目前为止宾夕法尼亚州［2］、西欧［3］和亚太［4］眼疾学就会发布新闻的慢性HIV（CHB）诊治Guide（以下前身宾夕法尼亚州Guide、西欧Guide和亚太Guide）关于自体耐受期CHB（IT-CHB）格外高血压的定义及化疗的延揽异议不完全一致：宾夕法尼亚州Guide［2］中的ALT短时间数值上限（ULN）成年为30 U/L，未婚为25 U/L；西欧和亚太Guide中的ALT ULN**皆为40 U/L。关于IT-CHB定义，宾夕法尼亚州Guide：HBV DNA＞106 IU/ml，ALT短时间；西欧Guide：HBV DNA＞107 IU/ml，ALT持续短时间；亚太Guide：HBV DNA＞20 000 IU/ml，ALT 1~2×ULN。关于IT-CHB化疗的延揽异议，宾夕法尼亚州和亚太Guide皆只延揽对肾脏活体显示中的度/重度上皮细胞（A3）或显着溃疡（F2）的IT-CHB格外高血压化疗；西欧Guide则延揽增大IT-CHB化疗指征：即年岁＞30岁，或有肾脏肿瘤（HCC）/并发症的有，或有肾脏外表现的IT-CHB格外高血压，即使ALT和肾脏活体短时间，也可以化疗。

2020年5年末，Jeng等［5］在“理可不增大CHB化疗指征”一文中的明确提出，对有稍微/方面性眼疾论据的灰区（即HBV DNA＜106 IU/ml）或年岁＞40岁的IT-CHB格外高血压透过抗原化疗，较宾夕法尼亚州Guide增大了化疗指征。2020年9年末，中的国日本和长崎10名专家联合发表关于启动时CHB化疗远东专家异议［6］，延揽ALT ULN成年为30 U/L，未婚为19 U/L，对ALT≥1×ULN格外高血压，延揽抗原化疗。该专家异议增大了颇为一部分IT-CHB格外高血压的抗原化疗。

宾夕法尼亚州、西欧和亚太Guide不延揽对IT-CHB化疗的原因是：（1）IT-CHB是良性病症期，不起因并发症和HCC或起因率很低［7-12］；（2）IT-CHB格外高血压的肾脏第三活体无或轻微上皮细胞和/或溃疡［2,9,13-14］；（3）治果欠，大多起因HBeAg血清学变换或HBsAg遗忘［5,15-19］；可自发自体依靠达到HBeAg血清学变换［8,20-21］；（4）IT-CHB格外高血压多为青年人，对一直抗原化疗依从性欠，易起因病原体性［12,22］。

2015年，Bertoletti等［23］对HBV病毒感染自体耐受期方法论明确提出抗议，视为这是老方法论，依赖于自体学论据。2016年，Gastroenterology周报第三组织专家对“自体耐受期方法论”透过了谈论［24-28］。Bertoletti等［23-25,28］视为不可不称作IT-CHB，建议改为“格外高复制低上皮细胞期（HRLI）”，原因是：（1）在胎儿要到期已存在效可不和调节自体这样的话；（2）男婴和婴儿可产生病原体抗原T胸腺这样的话；（3）男婴和婴儿的自体系统本身并无毛病；（4）儿童在1岁内注射HIV接种有效地；（5）不同期HIV格外高血压（还包括自体耐受期）皆有HBV抗原T胸腺这样的话、HBV DNA紧密结合和了了肾脏增量，说明心肌梗塞起因要到就启动时。但Milich［26］和Liaw等［27］视为将IT-CHB易名为HRLI的论据尚不充分。2017年西欧Guide首先将IT-CHB年末易名为“HBeAg乙型肾脏炎慢性HBV病毒感染”。

自2018年以来，特别是2020年，多位学者［29-33］明确提出，可不对HBV自体耐受期格外高血压化疗，以增格外高其起因并发症和HCC的风险，原因如下。

Mason等［24］测定26可有慢性HBV病毒HIV，其中的9可有IT-CHB格外高血压、10可有HBeAg乙型肾脏炎CHB格外高血压、7可有HBeAg乙型肾脏炎CHB格外高血压，辨认出IT-CHB格外高血压与HBeAg乙型肾脏炎和乙型肾脏炎CHB格外高血压一样，也可测定到HBV DNA紧密结合、肾脏特异性、了了肾脏增量、HBV抗原T胸腺这样的话以及肾脏损伤。Chu等［8］随访240可有IT-CHB格外高血压17年，并发症会有起因率为12.6%。Chen等［34］随访251可有IT-CHB格外高血压13年，HCC会有起因率为5.1%。Beasley等［35］前瞻性随访22 707可有40~59岁中的国台湾成年，其中的15.2%为HBsAg病毒病毒感染，平皆随访3.3年，HBsAg病毒病毒感染的HCC发病（1158/10都来年）总体格外高于非病毒病毒感染（5/10都来年）。Sun等［36］归纳现状161个病症受控点1990年—2014年的HCC发病资料辨认出，无论是大都市还是农村，成年和未婚HCC发病皆随年岁快速增长而显着升格外高，特别是在30岁以后（由此可知1）。HCC的起因是一个一直发展致病过程，说明要到在30岁以前HCC起因要到就启动时［35］。

由此可知1 现状1990年—2014年161个病症受控点城乡**HCC年岁死亡者专率［36］

Kim等［37］归纳日本所私立大学三甲的医院2000年—2013年病可有链表，其中的未能化疗的IT-CHB格外高血压413可有、核苷(硫酸)类似若无（NAs）化疗的自体活动期CHB格外高血压1497可有，%-，未能化疗的IT-CHB格外高血压10年会有HCC发病和死亡者/开腹起因率（共有12.7%和9.7%）总体格外高于化疗的自体活动期CHB格外高血压（共有6.1%和3.4%）（P数值共有0.001、0.001）。

既往虽有新闻报道［2,9,13-14］，IT-CHB格外高血压的肾脏第三活体无或轻微上皮细胞和/或溃疡，但近些年有多篇新闻报道［9,38-44］表明，28%~49%的IT-CHB格外高血压有显着的肾脏上皮细胞坏死和肾脏溃疡（≥G2/S2）病理学改变（表1）。

既往曾新闻报道［5,15-19］，IT-CHB格外高血压给予抗原治果较欠，大多起因HBeAg血清学变换或HBsAg遗忘。但近些年有多项史学研究［45-47］显示，分析方法NAs化疗IT-CHB格外高血压，虽然HBeAg血清学变换或HBsAg遗忘率低，但增格外高血清HBV DNA素质效果总体。Chan等［45］用替诺福韦酯（TDF）或TDF/恩曲他滨（FTC）分别化疗64可有和62可有IT-CHB格外高血压，半数为33岁，89%为亚洲人，B和C子代占93%，99%为HBeAg乙型肾脏炎，HBV DNA素质为8.41 log10 IU/ml,化疗至192就有，TDF第三组55%(35/64)、TDF/FTC第三组76%(47/62) 格外高血压的HBV DNA素质降至＜69 IU/ml，与曲率半径尤其有总体欠异（P=0.016）。Pan等［46］和Jourdain等［47］曾于在IT-CHB新生儿中的，筹划TDF预防HBV诊疗传播的格外高血压史学研究，将IT-CHB新生儿随机可分化疗第三组和依此第三组，Pan等［46］于孕30~32周至产妇4周，Jourdain等［47］于孕28周至产妇2周，分别给予各第三组新生儿TDF或口服，产妇时（即化疗8~12周）测定所有新生儿HBV DNA，%-TDF第三组HBV DNA素质分别下降4.7 log IU/ml和4.0 log IU/ml，而口服第三组HBV DNA素质无下降，仍维持在曲率半径素质。日本Chang等［48］筹划了一项政府机构多中的心回顾性史学研究，归纳2006年1年末—2016年3年末日本8所大型的医院共计484可有IT-CHB格外高血压（HBeAg乙型肾脏炎、HBV DNA素质＞20 000 IU/ml，ALT素质＜40 U/L、无并发症），其中的87可有给予抗原化疗，397可有未能给予抗原化疗作为依此，经倾向记扣除对归纳，10年间化疗第三组会有HCC及并发症起因率总体最低依此第三组（P数值共有0.046、0.015）（由此可知2）。

由此可知2 日本多中的心IT-CHB格外高血压抗原化疗回顾性归纳HCC及并发症会有起因率［48］

HBV DNA素质是HCC起因的独立生命危险因素，增格外高血清HBV DNA素质可总体增加HCC起因风险。Chen等［49］对基于社区1991年—1992年入第三组的3653可有（30~65岁）HBsAg乙型肾脏炎者前瞻性链表，平皆随访11.4年，辨认出其会有HCC起因率与入第三组时HBV DNA素质有关，入第三组时HBV DNA素质＜300、300~9999、10 000~99 999、100 000~999 999和≥1 000 000 解码/ml格外高血压HCC会有起因率共有1.30%、1.37%、3.57%、12.17%和14.89%，随HBV DNA素质上升而总体升格外高。

各国Guide［2-4,50］指出，化疗CHB的目的是：最大限度地一直抑制HBV复制，加重肾脏上皮细胞坏死及肾脏纤维第三组织发炎，延缓和增加肾脏功能衰竭、并发症惜代偿、HCC和其他并发症的起因，提格外高格外高血压贫困质量，延长其存活时间，而不仅仅是为了个别HBV标志若无的变换或遗忘。因此，从增格外高并发症和HCC风险来看，NAs化疗IT-CHB格外高血压的效果是总体的。

（1）现有HIV口服抗病若无恩替卡韦（ETV）、TDF、富马硫酸丙酚替诺福韦（TAF）一直化疗安全性好、病原体性起因率低［51-59］：ETV 5年会有病原体性起因率仅为1.2%［53］；TDF 8年未能辨认出病原体性［55］；TAF 3年无病原体性［58-59］。

（2）一直化疗依从性欠，不能作为不化疗的原因，因CHB格外高血压和其他慢性病症格外高血压也即可一直化疗，化疗的依从性可通过健康教育等措施进一步提格外高［31,60-61］。

（3）化疗实用性格外高。目前为止HIV抗病若无的化疗费最低受控费，且IT-CHB格外高血压对受控依从性欠。据新闻报道［19，62］，近61%的HCC格外高血压为首次就诊，说明这些格外高血压既往未能给予受控。

（4）对IT-CHB格外高血压抗原化疗可增格外高HBV素质传播和诊疗传播，并可增加HIV歧视［46-47,63-64］。

（5）对IT-CHB格外高血压化疗可进一步提格外高HIV诊断率和化疗率［30，32，65］，实现世界卫生第三组织明确提出的到2030年扫除HIV公共服务威胁的目标［66］。

鉴于（1） IT-CHB不是良性病症期；（2）对IT-CHB格外高血压化疗可增格外高并发症和HCC的起因；（3）一线用药抗原战斗能力强，病原体性起因率低，一直化疗安全有效地；（4）化疗费最低受控费，实用性格外高；（5）可增格外高HBV素质传播和诊疗传播，增加HIV歧视；（6）可进一步提格外高HIV诊断率和化疗率，实现世界卫生第三组织明确提出的到2030年扫除HIV公共威胁的目标。因此，可不增大对IT-CHB格外高血压的化疗。同时，可不筹划对IT-CHB格外高血压化疗的史学研究，提供者格外多的循证医学论据，如（1）回顾性前瞻性链表史学研究：尤其IT-CHB化疗第三组、未能化疗第三组和HBeAg乙型肾脏炎自体稍微HIV化疗第三组会有并发症起因率、HCC发病、开腹率及发病；（2）前瞻性链表史学研究：尤其3第三组会有并发症起因率、HCC发病、开腹率及发病；（3）格外高血压史学研究：尤其2第三组会有并发症起因率、HCC发病、开腹率及发病等。

参考文献:

［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)

中的华医学就会病毒感染病文凭就会, 中的华医学就会眼疾文凭就会. 慢性HIV防治Guide(2019年版)［J］. 临床肾脏胆病周报, 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.

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