可以让更多的人停止使用NRTI进行HBV吗？来自48周研究的提示

StephenW

Can More People Stops NRTIs for HBV?Hints From a 48-Week Study

A prospective study of nucleot(s)ide analogue discontinuation innon-cirrhotic HBeAg-negative chronic hepatitis B patients: interim analysis atweek 48 demonstrates profound reductions of HBsAg associated with ALT flare   

EASL 2020, Digital International Liver Congress, August 27-29, 2020

Mark Mascolini

Stopping nucleot(s)ide analogs (NRTIs) in noncirrhotic hepatitis B e-antigen (HBeAg)-negativepeople with chronic HBV infection always led to virologic relapse in an ongoingstudy, but 5% of participants had HBsAg loss within 48 weeks [1]. This interimanalysis linked HBsAg loss to HBsAg below 10 IU/mL before stopping therapy. Ninein 10 participants remain off treatment at 48 weeks. Australian researchers whoconducted the NA-STOP study believe their results suggest that treatmentwithdrawal may be appropriate for certain people on long-term NRTI therapy.

HBV treatment guidelines recommend indefinite NRTI therapy for people withHBeAg-negative chronic HBV infection. (HBeAg indicates active, transmissibleHBV infection.) But some people who stop long-term NRTIs have sustainedvirologic suppression off treatment, and 6% to 55% have HBsAg loss. (HBsAgindicates current HBV infection.) International guidelines differ on when NRTIdiscontinuation may be tried in HBeAg-negative people with chronic HBV.

To explore these dynamics, Australian investigators mounted NA-STOP, aprospective multicenter study of stopping NRTIs in HBV patients withoutcirrhosis who attain long-term virologic suppression on treatment. The studyincluded HBeAg-negative, noncirrhotic patients with virologic suppression forat least 18 months on NRTI therapy taken without interruption for at least 2years. The protocol called for restarting NRTIs if (1) HBV DNA rose above 2000IU/mL with (a) either alanine aminotransferase (ALT) more than 5 times the upperlimit of normal (ULN) for at least 16 consecutive weeks, or (b) ALT more than10 times ULN for at least 8 consecutive weeks, or with (2) InternationalNormalized Ratio (INR) at or above 1.5, (3) bilirubin more than 2 times ULN, (4)any clinical feature of portal hypertension (ascites) or hepaticencephalopathy, or (5) investigator discretion.

Primary analysis will come 96 weeks after NRTIs stop. This preliminary 48-weekanalysis involved 107 of 111 participants. When NA-STOP members enrolled, theyhad a median age of 56 years, 58% were men, 85% were Asian, and 9% were Caucasian.No patients had cirrhosis, and median HBsAg stood at 705 IU/mL (interquartilerange [IQR] 214 to 2325).

All participants experienced virologic relapse when treatment stopped, with amedian time to HBV reactivation of 8 weeks (IQR 4 to 12). Relapse occurredsignificantly earlier with tenofovir disoproxil fumarate (TDF) than withentecavir (P = 0.008). Twenty-three study participants (21% of 107) hadpeak HBV DNA below 2000 IU/mL, 24 (22%) had peak HBV DNA between 2000 and20,000 IU/mL, 26 (24%) peaked at 20,000 to 200,000 IU/mL, and 34 (32%) peakedabove 200,000 IU/mL.

The researchers observed two ALT flare patterns: a “good” flare indicated bymore than a 1-log (10-fold) drop in HBsAg and HBV DNA control), and a “bad”flare with less than a 10-fold drop in HBsAg and persistent or recurrent HBVDNA. Five study participants (4.7% of 107) had “good” flares and 21 (19.6%) had“bad” flares. Four of 5 people with “good” flares had an HBsAg below 10 IU/mL48 weeks after NRTI withdrawal. In those people, ALT rapidly returned to normaland no secondary ALT flares occurred.

All 5 people with “good” flares attained HBsAg loss. Only one variable predictedHBsAg loss: HBsAg below 10 IU/mL before treatment stopped (P < 0.001vs participants with an on-treatment HBsAg above 10 IU/mL). At week 48, 5% ofparticipants had HBsAg below 10 IU/mL, 17% were between 10 and 100 IU/mL, 40%were between 100 and 1000 IU/mL, and 36% were above 1000 IU/mL.

At the 48-week point, 11% of participants had restarted NRTI therapy. At 48weeks, 72% of participants had an ALT below 2 times ULN and 41% had HBV DNAbelow 2000 IU/mL.

NRTI withdrawal proved largely safe through 48 weeks. At that point only 4people (4%) had bilirubin more than 2 times ULN. No one had an InternationalNormalized Ratio (ILN) above 1.5, ascites, hepatic encephalopathy, orhepatocellular carcinoma.

Summing up, the NA-STOP team stressed that 89% of people remained off treatment48 weeks after stopping NRTI therapy, and 41% had HBV DNA below 2000 IU/mL. Follow-upwill continue through 96 weeks. Five people had HBsAg loss at 48 weeks, and allhad an HBsAg below 10 IU/mL before stopping therapy. The researchers believetheir findings “support a place for treatment withdrawal in selected patientson long-term [NRTI] therapy.”

Reference
1. Hall S, Burns G, Levy M, et al. A prospective studyof nucleot(s)ide analogue discontinuation in non-cirrhotic HBeAg-negativechronic hepatitis B patients: interim analysis at week 48 demonstrates profoundreductions of HBsAg associated with ALT flare. EASL 2020, DigitalInternational Liver Congress, August 27-29, 2020. Abstract AS095.

StephenW

可以让更多的人停止使用NRTI进行HBV吗？来自48周研究的提示

非肝硬化HBeAg阴性慢性乙型肝炎患者核苷酸类似物停药的前瞻性研究：第48周的中期分析表明，与ALT发作相关的HBsAg明显降低

EASL 2020，数字国际肝脏大会，2020年8月27日至29日

马克·马斯科利尼

在正在进行的一项研究中，在慢性乙型肝炎病毒感染的非肝硬化乙型肝炎电子抗原（HBeAg）阴性患者中停止核苷酸类似物（NRTIs）总是导致病毒学复发，但是5％的参与者在48周内出现HBsAg丢失[1]。 ]。这项中期分析将HBsAg丢失与停止治疗前低于10 IU / mL的HBsAg联系起来。每10位参与者中有9位在48周后仍未接受治疗。进行NA-STOP研究的澳大利亚研究人员认为，他们的结果表明，退出治疗可能适合某些接受长期NRTI治疗的人。

HBV治疗指南建议对HBeAg阴性的慢性HBV感染者进行无限期NRTI治疗。 （HBeAg表示活跃的，可传播的HBV感染。）但是，一些停止长期服用NRTIs的人在治疗后一直受到病毒学抑制，而6％至55％的HBsAg丢失。 （HBsAg表示当前是HBV感染。）国际指南对何时在慢性HBV的HBeAg阴性人群中尝试NRTI终止治疗有所不同。

为了探索这些动态，澳大利亚研究人员进行了NA-STOP研究，这是一项前瞻性多中心研究，目的是在治疗中获得长期病毒学抑制作用的无肝硬化的HBV患者中，停止NRTIs治疗。该研究包括接受NRTI治疗的HBeAg阴性，非肝硬化病毒感染至少18个月的患者，服用该药物至少2年而无间断。如果（1）HBV DNA升至2000 IU / mL以上，并且（a）至少连续16周的丙氨酸转氨酶（ALT）超过正常上限（ULN）的5倍以上，或者（b） ）ALT至少连续8周超过ULN的10倍，或（2）国际标准化比率（INR）等于或高于1.5，（3）胆红素超过ULN的2倍，（4）门脉高压的任何临床特征（腹水）或肝性脑病，或（5）研究者酌情决定。

NRTI停用后96周将进行初步分析。这项为期48周的初步分析涉及111位参与者中的107位。当NA-STOP成员入组时，他们的中位年龄为56岁，男性为58％，亚裔为85％，白人为9％。无肝硬化患者，HBsAg中位数为705 IU / mL（四分位间距[IQR] 214至2325）。

当治疗停止时，所有参与者都经历了病毒学复发，HBV复活的中位时间为8周（IQR 4至12）。替诺福韦富马酸替诺福韦酯（TDF）的发生明显早于恩替卡韦（P = 0.008）。 23名研究参与者（107％中的21％）的HBV DNA峰值低于2000 IU / mL，24（22％）HBV DNA峰值在2000至20,000 IU / mL之间，26（24％）峰值在20,000至200,000 IU / mL毫升，其中34（32％）的峰值超过200,000 IU / mL。

研究人员观察到了两种ALT耀斑模式：“好”耀斑表示HBsAg和HBV DNA对照下降超过1个对数（10倍），而“坏”耀斑下降不到10倍。 HBsAg和持续性或复发性HBV DNA。五名研究参与者（占107％的4.7％）有“良好”的耀斑，而21名（19.6％）具有“不良”的耀斑。在NRTI戒断后48周，有“良好”发作的5个人中有4个人的HBsAg低于10 IU / mL。在这些人中，ALT迅速恢复正常，没有继发性ALT发作。

所有5个“良好”耀斑患者均HBsAg丢失。只有一个变量预测HBsAg丧失：治疗停止前HBsAg低于10 IU / mL（与接受治疗的HBsAg高于10 IU / mL的参与者相比，P <0.001）。在第48周时，有5％的参与者HBsAg低于10 IU / mL，17％的HBsAg在10 IU / mL与100 IU / mL之间，40％的HBsAg在100 IU / mL与1000 IU / mL之间，有36％的HBsAg高于1000 IU / mL。

在48周时，有11％的参与者重新开始了NRTI治疗。在第48周时，72％的受试者的ALT低于ULN的2倍，而41％的受试者的HBV DNA低于2000 IU / mL。

NRTI撤出证明在48周内基本上是安全的。那时只有4人（4％）的胆红素超过正常值上限的2倍。没有人的国际标准化比率（ILN）高于1.5，有腹水，肝性脑病或肝细胞癌。

总结而言，NA-STOP小组强调，停止NRTI治疗48周后仍有89％的人停止治疗，而41％的HBV DNA低于2000 IU / mL。随访将持续96周。五人在48周时HBsAg丢失，并且所有人在停止治疗前的HBsAg均低于10 IU / mL。研究人员认为，他们的发现“为某些接受长期[NRTI]治疗的患者提供了退出治疗的机会。”
参考
1. Hall S，Burns G，Levy M等。 对非肝硬化性HBeAg阴性的慢性乙型肝炎患者进行核苷酸类似物停药的前瞻性研究：第48周的中期分析表明，与ALT发作相关的HBsAg明显降低。 EASL 2020，数字国际肝脏大会，2020年8月27-29日。摘要AS095。