改变 HBV 管理模式

StephenW

改变 HBV 管理模式
卷。 26，第 3 期（2021 年 12 月）
Tanyaporn Chantarojanasiri，医学博士

Zaigham Abbas，FCPS，FRCP，FACP，FACG，AGAF
肝肠内科教授兼系主任
Dr. Ziauddin 克利夫顿大学医院
巴基斯坦卡拉奇

使用目前可用的核苷（酸）类似物（NA）药物，HBsAg 消失和血清转换是一项艰巨的任务，可能需要无限期的治疗。为了确定乙肝治疗的时长，我们需要定义其他最佳终点。 HBeAg 消失或血清转换可作为 HBeAg 阳性慢性乙型肝炎 (CHB) 的终点，但即使在 HBeAg 血清转换后也需要巩固治疗。 HBeAg 阴性患者的 HBV DNA 抑制需要达到什么水平和多长时间仍未得到解答。对于所有晚期纤维化或肝硬化患者，应继续治疗。因此，患者的选择和教育对于停止治疗的决定至关重要。新出现的数据使得不治疗免疫耐受患者的建议存在争议。我们特此详细解决这些问题（图 1）。

图 1：改变 HBV 管理模式

治疗免疫耐受患者

众所周知，ALT 水平升高与 HBeAg 阳性 CHB 患者的纤维化有关。抗病毒治疗可逆转炎症、减少纤维化、降低 HCC 死亡率并改善门静脉高压症和无移植生存率。然而，目前的 NA 治疗存在长期抑制的局限性。长期治疗存在一些安全问题。在高病毒血症 HBeAg 阳性患者中仅观察到部分病毒学反应。长期 NA 治疗期间仍存在残余 HCC 风险。此外，NA 停止规则仍不清楚； HBsAg 丢失率低，并且该疗法不能根除 cccDNA 或整合的 HBV DNA。治疗时间长（在某些情况下是终生的）与高成本、潜在的耐药性和不良事件有关。由于这些原因，指南不建议治疗免疫耐受患者。

然而，10% ALT 正常的 HBeAg 阳性患者有晚期纤维化。 REVEAL 研究表明，较高的 HBV DNA 水平与肝硬化和肝细胞癌 (HCC) 的风险增加相关。 1 在不符合 HBV 指南中规定的 HBV 治疗标准的患者中，HCC 的风险仍然较高。 2 HBV 治疗可降低疾病进展的风险，包括失代偿和肝移植。3 因此，那些未接受治疗的人需要仔细监测。较新的研究预示着免疫耐受患者的潜在范式转变。最近的一些数据表明，治疗此类患者可能会降低肝纤维化进展和肝细胞癌的风险。 4

在韩国历史队列研究中，对 2000-2013 年间在三级转诊医院就诊的无肝硬化患者进行了随访。该队列包括免疫耐受、未治疗 (n = 413) 和免疫活性 (ALT ≥ 80 IU/mL) 治疗 (n = 1497) 患者。免疫耐受患者 10 年后 HCC 的累积发生率为 12.7%，接受治疗的患者为 6.1%。对于死亡或肝移植，数字分别为 9.7% 和 3.4%。 5 有几个观点支持治疗免疫耐受的慢性 HBV 感染：

    高水平病毒血症可能是致癌的。
    几乎所有患者都可以实现显着的病毒抑制，即使不完全抑制。
    过渡到免疫活性阶段可能无法识别。
    一些ALT正常的患者有纤维化。
    年轻病毒血症患者的传播风险很高。

在讨论了基本原理和局限性之后，可以在有纤维化证据的个体免疫耐受患者中开始治疗。除非发生血清转化，否则在没有新疗法的情况下必须将治疗视为无限期。应考虑进行诊断性肝活检或通过瞬时弹性成像估计纤维化，以评估纤维化程度，从而做出治疗决定。如果患有免疫耐受性疾病的患者有F2或更多纤维化，将建议进行抗病毒治疗。
何时停止核苷（酸）类似物治疗？

HBeAg 阳性 CHB 的 NA 停药

指南建议在确认 HBsAg 消失后停用 NA，无论是否有抗 HBs 血清学转换。6 对于 HBeAg 血清学转换稳定且 HBV DNA 检测不到的非肝硬化 HBeAg 阳性 CHB 患者，并且完成至少 12 个月的治疗，可以停止治疗。巩固治疗。有必要进行密切的 NA 后监测。 HBeAg 血清转换后高加索乙型肝炎患者停止 NA 治疗与高复发率相关。在一项研究中，在中位巩固治疗 8 个月后停止治疗的 62 名患者中，有 30 人复发。7 巩固持续时间越长，复发率越低。在一项研究中，在中位巩固治疗 8 个月后停止治疗的 62 名患者中，有 30 人复发。7 巩固持续时间越长，复发率越低。在一项研究中，在不到 12 个月的巩固治疗中停止治疗的患者中，只有 26% 的患者维持 HBeAg 血清学转换和无法检测到 HBV DNA。在超过 18 个月后停止治疗的人中，这种反应率上升到 71%。8 复发率在 40 岁以上的老年人群中更为常见。巩固持续时间超过 12 个月，尤其是老年患者更可取。 9 在停止 NA 治疗后，每 3 个月监测复发性病毒血症、ALT 发作、血清逆转和失代偿，至少 12 个月。9 对于晚期纤维化或肝硬化患者，治疗无限期，除非存在强有力的终止治疗的理由。

HBeAg 阴性 CHB 的 NA 停药

几项研究表明，在 HBsAg 消失后，无论是否有血清学转换，停用 NA 是 NA 治疗的最佳可能停止规则。它是安全有效的，并且 HBsAg 的消失可以在治疗后持续。然而，单独使用 NA 不太可能实现 HBsAg 消失。我们可以在 HBsAg 消失之前停止 NA 吗？最近的指南建议，如果遵循严格的 NA 后监测和足够的再治疗安全规则，可以考虑在选定的非肝硬化 HBeAg 阴性患者中停用 NA，这些患者已经实现了长期病毒学抑制（>3 ​​年）。 6 计算退出NA 导致大多数患者的 HBV DNA 复发。有证据表明，这种病毒抗原的突然暴露可以触发一些患者的免疫控制，这可能导致 HBsAg 消失或一种具有持续低 HBV DNA 水平和正常 ALT 的免疫控制形式。 10

DARING-B 研究包括 57 名 HBeAg 阴性 CHB 非肝硬化患者，这些患者在中位病毒学缓解 5.3 年后停止恩替卡韦或替诺福韦 DF 治疗并继续密切随访。如果他们满足预定标准，他们将接受恩替卡韦或富马酸替诺福韦二吡呋酯 (TDF) 治疗。在 3 个月和 12 个月时，再治疗的累积概率分别为 18% 和 26%。在 6、12 和 18 个月时，HBsAg 累积消失率分别为 5%、16% 和 25%，在停止治疗时 HBsAg 水平较低的患者中更高。 11 在 FINITE 研究中，接受过治疗的非肝硬化 HBeAg 阴性患者TDF ≥4 年，HBV DNA 抑制≥3.5 年，被随机分配到停止 (n=21) 或继续 (n=21) TDF 单药治疗。 12 在停止 TDF 治疗的患者中，62% (n= 13) 在第 144 周仍处于非治疗状态。19% (4/21) 在第 144 周实现 HBsAg 消失。

当停止 NA 时，病毒学复发几乎是普遍的。在数周至数月的“滞后期”之后，“再激活期”开始，大多数患者表现出一定程度的 HBV DNA 反弹，随后通常伴随着 ALT 水平的升高。在此阶段可能会出现严重的免疫发作，需要立即重新治疗（ALT > 10 x ULN 或 ALT > 5 x ULN 和胆红素 > 2 mg/dL 和/或凝血酶原时间延长）。在第三阶段，一些短暂性发作后的患者进入低复制“携带者”状态。有些保留了一定程度的疾病活动，需要再治疗（ALT > 3x ULN 和 HBV DNA > 100,000 IU/mL），而另一些可能仍处于中间状态，ALT > ULN 和 HBV DNA > 2000 IU/mL ≥ 3-6 个月并且以后需要治疗。这些截断需要在未来的研究中进行验证。 13, 14

总之，对于接受有效 NA 超过 4 年的非肝硬化 HBeAg 阴性 CHB 患者，可以停止治疗。 6个月后复发的可能性降低。尽管常见病毒学复发，但大多数患者，尤其是治疗前有轻度至中度纤维化的患者，至少在前 18 个月内没有再治疗，其中很大一部分患者清除了 HBsAg，并且大多数患者最终进入非活动性携带者状态。因此，NA 退出策略似乎很有希望，但现在推荐作为护理标准还为时过早。 20% 实现 HBsAg 消失； 60% 仍然停止治疗。由于耀斑可能很严重，因此需要密切监测。
区分非活动携带者与 HBeAg 阴性 CHB

确定真正的非活动携带者状态对于决定是开始治疗还是继续监测至关重要。 HBeAg 阴性 CHB 患者的 HBV DNA 和 ALT 波动可能与具有进展和 HCC 风险的非活动携带者状态相似。定量 HBsAg 是肝细胞内共价闭合环状 DNA 的数量和活性的标志物。 HBV DNA 加上定量 (q) HBsAg 可以帮助识别真正的非活动携带者。 HBV DNA ≤ 2000 IU/mL 和 qHBsAg < 1000 IU/mL 可识别非活动携带者，诊断准确率为 94.3%。15 包含 HBeAg、HBcAg 和核心相关蛋白 (p22cr) 的乙型肝炎核心相关抗原 (HBcrAg) 见于没有 HBV DNA 的病毒粒子样颗粒。它可能反映肝内 cccDNA 转录活性和水平。16 在 HBeAg 阴性患者中，HBcrAg 可能有助于区分非活动携带者和活动性疾病携带者。 HBV 基因型 D 的非活动或静止携带者患者的 HBcrAg 水平通常 <3 log U/mL。17 区分非活动携带者的另一个标志物是 HBV RNA，它是 cccDNA 转录的可测量标志物。18
新药

在不同阶段阻断 HBV 生命周期的广谱抗病毒药物正在临床开发中，包括进入抑制剂、cccDNA 破坏剂/沉默剂、翻译抑制剂、衣壳组装调节剂、聚合酶抑制剂和分泌抑制剂。 19 Bulevertide 与牛磺胆酸钠共转运结合多肽 (NTCP)，一种允许 HBV 进入肝细胞的摄取细胞膜转运蛋白。该药物最近在欧洲被批准用于治疗 delta 病毒血症患者。20 该药物正在进行 III 期研究，在乙型肝炎患者中进行单药治疗或与干扰素联合治疗的研究。乙肝治疗的进展将影响今后的管理方针。

StephenW

Changing Paradigms in HBV Management
Vol. 26, Issue #3 (December 2021)
Tanyaporn Chantarojanasiri, MD        

Zaigham Abbas, FCPS, FRCP, FACP, FACG, AGAF
Professor and Head, Department of Hepato-Gastroenterology
Dr. Ziauddin University Hospital Clifton
Karachi, Pakistan

HBsAg loss and seroconversion is a difficult task to achieve with the currently available nucleos(t)ide analogue (NA) drugs and treatment may be required for an indefinite duration. To determine the length of hepatitis B therapy, we need to define other optimal endpoints. HBeAg loss or seroconversion may be taken as an endpoint in HBeAg positive chronic hepatitis B (CHB) but consolidation therapy is required even after HBeAg seroconversion. To what level and how long HBV DNA suppression in HBeAg negative patients is required remains unanswered. For all patients with advanced fibrosis or cirrhosis, therapy should continue. Thus, patient selection and education are critical in decisions addressing cessation of therapy. Emerging data has made the recommendation of not treating immunotolerant patients controversial. We herewith address these issues with some detail (Figure 1).

Figure 1: Changing Paradigms in HBV Management

Treating immune-tolerant patients

It is well known that elevated ALT level is associated with fibrosis in patients with HBeAg-positive CHB. Antiviral therapy leads to reversal of inflammation, regression of fibrosis, reduction of HCC mortality and improves portal hypertension and transplant-free survival. However, there are limitations of long-term suppression with current NA therapy. There are some safety issues related to long-term treatment. Only partial virologic response is seen in highly viremic HBeAg positive patients. Residual HCC risk remains during long-term NA therapy. Moreover, NA stopping rules remain unclear; there are low HBsAg loss rates and the therapy does not eradicate cccDNA or integrated HBV DNA. The long duration of treatment (life-long in some cases) is associated with high costs, potential drug resistance and adverse events. For these reasons, treating immune-tolerant patients is not recommended by the guidelines.   

However, 10% of HBeAg-positive patients with normal ALT have advanced fibrosis. REVEAL study showed that higher HBV DNA levels are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC).1 The risk of HCC remains elevated in patients who do not meet HBV therapy criteria laid down in the HBV guidelines.2 HBV treatment reduces the risk of disease progression including decompensation and liver transplant.3 So, those not on treatment require careful monitoring. Newer studies foretell a potential paradigm shift for immune-tolerant patients. Some recent data suggests treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.4

In the Historical Korean Cohort Study, patients without cirrhosis seen at a tertiary referral hospital between 2000-2013 were followed up. The cohort included immune-tolerant, untreated (n = 413) and immune-active (ALT ≥ 80 IU/mL) treated (n = 1497) patients. Cumulative incidence of HCC after 10 years was 12.7% in immunotolerant patients and 6.1% in treated patients. For death or liver transplantation, figures were 9.7% and 3.4%, respectively.5 There are several arguments in favor of treating immune-tolerant chronic HBV infection:

    High-level viremia can be oncogenic.
    Marked viral suppression, even if not complete, can be achieved in nearly all patients.
    Transition to the immune-active phase may go unrecognized.
    Some patients with normal ALT have fibrosis.
    There is a high risk of transmission by young viremic patients.

After discussion of rationale and limitations, treatment may be initiated in individual immune-tolerant patients with evidence of fibrosis. Treatment must be regarded as indefinite in absence of new therapies unless seroconversion occurs. Diagnostic liver biopsy or estimation of fibrosis by transient elastography should be considered to assess the degree of fibrosis so that a treatment decision can be rendered. If patients with the immune-tolerant disease have F2 fibrosis or more, antiviral therapy will be suggested.
When to discontinue nucleos(t)ide analogue therapy?

NA discontinuation in HBeAg positive CHB

Guidelines suggest that NA should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion.6 Therapy may be stopped in non-cirrhotic HBeAg positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy. Close post-NA monitoring is warranted. Stopping NA treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates.In one study, of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed.7 Fewer relapses occur with a longer duration of consolidation. In one study, patients who stopped treatment in less than 12 months of consolidation, only 26% maintained HBeAg seroconversion and undetectable HBV DNA. This response rate rose to 71% among those who stopped after more than 18 months.8 Relapses are seen more in the older age group of more than 40 years. Duration of consolidation longer than 12 months especially in older patients is preferable.9 After stopping NA therapy monitor for recurrent viremia, ALT flares, seroreversion, and decompensation every 3 months for at least 12 months.9 In those with advanced fibrosis or cirrhosis, treat indefinitely unless a strong competing rationale for treatment discontinuation exists.

NA discontinuation in HBeAg negative CHB

Several studies have shown that NA discontinuation after HBsAg loss with or without seroconversion is the best possible stopping rule for NA therapy. It is safe and effective and HBsAg loss is sustained off treatment. However, HBsAg loss is unlikely to be achieved with NA alone. Can we stop NA before HBsAg loss? Recent guidelines suggest that discontinuation of NA may be considered in selected non-cirrhotic HBeAg-negative patients who have achieved long-term virological suppression (>3 years) if close post-NA monitoring and adequate safety rules for retreatment are followed.6 Calculated withdrawal of NA leads to a relapse of HBV DNA in most patients. There is evidence that this sudden exposure of viral antigens can trigger immune control in some patients which may result in HBsAg loss or a form of immune control with sustained low HBV DNA levels and normal ALT.10

DARING-B study included 57 non-cirrhotic patients with HBeAg-negative CHB who stopped entecavir or tenofovir DF therapy after a median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir or tenofovir disoproxil fumarate (TDF) if they fulfilled predetermined criteria. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months. Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months, being higher in patients with lower HBsAg levels at treatment discontinuation.11 In the FINITE study, non-cirrhotic HBeAg-negative patients who had received TDF for ≥4 years, with suppressed HBV DNA for ≥3.5 years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy.12 Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to week 144. 19% (4/21) achieved HBsAg loss at week 144.

When stopping NA, a virologic relapse is nearly universal. After the “lag phase” for weeks to months, the “reactivation phase” starts where most patients show some level of HBV DNA rebound, which is often followed by an increase in ALT levels. Severe immune flares may occur in this phase and need immediate re-treatment (ALT > 10 x ULN or ALT > 5 x ULN and bilirubin > 2 mg/dL and/or prolonged prothrombin time). In the third phase, some patients after transient flares enter a low-replicative “carrier” state. Some retain a degree of disease activity requiring retreatment (ALT > 3x ULN and HBV DNA > 100,000 IU/mL) while others can still be in an intermediate state with ALT > ULN and HBV DNA > 2000 IU/mL for ≥ 3-6 months and require treatment later on. These cut off need validation in future studies.13, 14

In conclusion, therapy can be discontinued in non-cirrhotic HBeAg-negative CHB patients who have received effective NA for more than 4 years. The probability of relapse decreases after 6 months. Despite common virological relapses, most patients, particularly those with mild to moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, and a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state. So NA withdrawal strategies appear promising, but it is premature to recommend as the standard of care. 20% achieve HBsAg loss; 60% remain off therapy. Close monitoring is needed as flares can be severe.
Distinguishing inactive carriers from HBeAg-negative CHB

Identifying true inactive carrier status is essential to decide whether to start treatment or continue monitoring only. Fluctuating HBV DNA and ALT in HBeAg negative CHB patients may mimic inactive carrier status with risk of progression and HCC. Quantitative HBsAg is a marker for the amount and activity of covalently closed circular DNA inside hepatocytes. HBV DNA plus quantitative(q) HBsAg can help identify true inactive carriers. HBV DNA ≤ 2000 IU/mL and qHBsAg < 1000 IU/mL identifies inactive carriers with 94.3% diagnostic accuracy.15 Hepatitis B core-related antigen (HBcrAg) comprising HBeAg, HBcAg, and a core-related protein (p22cr) is found in virion-like particles without HBV DNA.It may reflect intrahepatic cccDNA transcriptional activity and levels.16 In HBeAg-negative patients, HBcrAg may help to distinguish between inactive carriers and those with active disease. Inactive or quiescent carriers patients of HBV genotype D usually have HBcrAg levels <3 log U/mL.17 Another marker to distinguish inactive carriers is HBV RNA that is a measurable marker of transcription of cccDNA.18
New drugs

A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors.19 Bulevertide binds to sodium taurocholate co-transporting polypeptide (NTCP), the uptake cell membrane transporter that allows HBV entrance into the hepatocyte. The drug has been recently approved in Europe as a treatment for viremic patients with hepatitis delta.20 The drug is undergoing phase III studies where monotherapy or in combination with interferon are investigated in patients with hepatitis B. The advances in hepatitis B therapeutics will influence the management guidelines in future.

StephenW

https://www.worldgastroenterolog ... s-in-hbv-management

lizyong22

乙肝人1949

以上，我都同意

齐欢畅

Changing Paradigms in HBV Management

Vol. 26, Issue #3 (December 2021)

Tanyaporn Chantarojanasiri, MD       
Zaigham Abbas, FCPS, FRCP, FACP, FACG, AGAF
Professor and Head, Department of Hepato-Gastroenterology
Dr. Ziauddin University Hospital Clifton
Karachi, Pakistan

HBsAg loss and seroconversion is a difficult task to achieve with the currently available nucleos(t)ide analogue (NA) drugs and treatment may be required for an indefinite duration. To determine the length of hepatitis B therapy, we need to define other optimal endpoints. HBeAg loss or seroconversion may be taken as an endpoint in HBeAg positive chronic hepatitis B (CHB) but consolidation therapy is required even after HBeAg seroconversion. To what level and how long HBV DNA suppression in HBeAg negative patients is required remains unanswered. For all patients with advanced fibrosis or cirrhosis, therapy should continue. Thus, patient selection and education are critical in decisions addressing cessation of therapy. Emerging data has made the recommendation of not treating immunotolerant patients controversial. We herewith address these issues with some detail (Figure 1).

Figure 1: Changing Paradigms in HBV Management



Treating immune-tolerant patients

It is well known that elevated ALT level is associated with fibrosis in patients with HBeAg-positive CHB. Antiviral therapy leads to reversal of inflammation, regression of fibrosis, reduction of HCC mortality and improves portal hypertension and transplant-free survival. However, there are limitations of long-term suppression with current NA therapy. There are some safety issues related to long-term treatment. Only partial virologic response is seen in highly viremic HBeAg positive patients. Residual HCC risk remains during long-term NA therapy. Moreover, NA stopping rules remain unclear; there are low HBsAg loss rates and the therapy does not eradicate cccDNA or integrated HBV DNA. The long duration of treatment (life-long in some cases) is associated with high costs, potential drug resistance and adverse events. For these reasons, treating immune-tolerant patients is not recommended by the guidelines.   

However, 10% of HBeAg-positive patients with normal ALT have advanced fibrosis. REVEAL study showed that higher HBV DNA levels are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC).1 The risk of HCC remains elevated in patients who do not meet HBV therapy criteria laid down in the HBV guidelines.2 HBV treatment reduces the risk of disease progression including decompensation and liver transplant.3 So, those not on treatment require careful monitoring. Newer studies foretell a potential paradigm shift for immune-tolerant patients. Some recent data suggests treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.4

In the Historical Korean Cohort Study, patients without cirrhosis seen at a tertiary referral hospital between 2000-2013 were followed up. The cohort included immune-tolerant, untreated (n = 413) and immune-active (ALT ≥ 80 IU/mL) treated (n = 1497) patients. Cumulative incidence of HCC after 10 years was 12.7% in immunotolerant patients and 6.1% in treated patients. For death or liver transplantation, figures were 9.7% and 3.4%, respectively.5 There are several arguments in favor of treating immune-tolerant chronic HBV infection:

High-level viremia can be oncogenic.
Marked viral suppression, even if not complete, can be achieved in nearly all patients.
Transition to the immune-active phase may go unrecognized.
Some patients with normal ALT have fibrosis.
There is a high risk of transmission by young viremic patients.
After discussion of rationale and limitations, treatment may be initiated in individual immune-tolerant patients with evidence of fibrosis. Treatment must be regarded as indefinite in absence of new therapies unless seroconversion occurs. Diagnostic liver biopsy or estimation of fibrosis by transient elastography should be considered to assess the degree of fibrosis so that a treatment decision can be rendered. If patients with the immune-tolerant disease have F2 fibrosis or more, antiviral therapy will be suggested.

When to discontinue nucleos(t)ide analogue therapy?

NA discontinuation in HBeAg positive CHB

Guidelines suggest that NA should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion.6 Therapy may be stopped in non-cirrhotic HBeAg positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy. Close post-NA monitoring is warranted. Stopping NA treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates. In one study, of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed.7 Fewer relapses occur with a longer duration of consolidation. In one study, patients who stopped treatment in less than 12 months of consolidation, only 26% maintained HBeAg seroconversion and undetectable HBV DNA. This response rate rose to 71% among those who stopped after more than 18 months.8 Relapses are seen more in the older age group of more than 40 years. Duration of consolidation longer than 12 months especially in older patients is preferable.9 After stopping NA therapy monitor for recurrent viremia, ALT flares, seroreversion, and decompensation every 3 months for at least 12 months.9 In those with advanced fibrosis or cirrhosis, treat indefinitely unless a strong competing rationale for treatment discontinuation exists.

NA discontinuation in HBeAg negative CHB

Several studies have shown that NA discontinuation after HBsAg loss with or without seroconversion is the best possible stopping rule for NA therapy. It is safe and effective and HBsAg loss is sustained off treatment. However, HBsAg loss is unlikely to be achieved with NA alone. Can we stop NA before HBsAg loss? Recent guidelines suggest that discontinuation of NA may be considered in selected non-cirrhotic HBeAg-negative patients who have achieved long-term virological suppression (>3 years) if close post-NA monitoring and adequate safety rules for retreatment are followed.6 Calculated withdrawal of NA leads to a relapse of HBV DNA in most patients. There is evidence that this sudden exposure of viral antigens can trigger immune control in some patients which may result in HBsAg loss or a form of immune control with sustained low HBV DNA levels and normal ALT.10

DARING-B study included 57 non-cirrhotic patients with HBeAg-negative CHB who stopped entecavir or tenofovir DF therapy after a median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir or tenofovir disoproxil fumarate (TDF) if they fulfilled predetermined criteria. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months. Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months, being higher in patients with lower HBsAg levels at treatment discontinuation.11 In the FINITE study, non-cirrhotic HBeAg-negative patients who had received TDF for ≥4 years, with suppressed HBV DNA for ≥3.5 years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy.12 Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to week 144. 19% (4/21) achieved HBsAg loss at week 144.

When stopping NA, a virologic relapse is nearly universal. After the “lag phase” for weeks to months, the “reactivation phase” starts where most patients show some level of HBV DNA rebound, which is often followed by an increase in ALT levels. Severe immune flares may occur in this phase and need immediate re-treatment (ALT > 10 x ULN or ALT > 5 x ULN and bilirubin > 2 mg/dL and/or prolonged prothrombin time). In the third phase, some patients after transient flares enter a low-replicative “carrier” state. Some retain a degree of disease activity requiring retreatment (ALT > 3x ULN and HBV DNA > 100,000 IU/mL) while others can still be in an intermediate state with ALT > ULN and HBV DNA > 2000 IU/mL for ≥ 3-6 months and require treatment later on. These cut off need validation in future studies.13, 14

In conclusion, therapy can be discontinued in non-cirrhotic HBeAg-negative CHB patients who have received effective NA for more than 4 years. The probability of relapse decreases after 6 months. Despite common virological relapses, most patients, particularly those with mild to moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, and a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state. So NA withdrawal strategies appear promising, but it is premature to recommend as the standard of care. 20% achieve HBsAg loss; 60% remain off therapy. Close monitoring is needed as flares can be severe.

Distinguishing inactive carriers from HBeAg-negative CHB

Identifying true inactive carrier status is essential to decide whether to start treatment or continue monitoring only. Fluctuating HBV DNA and ALT in HBeAg negative CHB patients may mimic inactive carrier status with risk of progression and HCC. Quantitative HBsAg is a marker for the amount and activity of covalently closed circular DNA inside hepatocytes. HBV DNA plus quantitative(q) HBsAg can help identify true inactive carriers. HBV DNA ≤ 2000 IU/mL and qHBsAg < 1000 IU/mL identifies inactive carriers with 94.3% diagnostic accuracy.15 Hepatitis B core-related antigen (HBcrAg) comprising HBeAg, HBcAg, and a core-related protein (p22cr) is found in virion-like particles without HBV DNA. It may reflect intrahepatic cccDNA transcriptional activity and levels.16 In HBeAg-negative patients, HBcrAg may help to distinguish between inactive carriers and those with active disease. Inactive or quiescent carriers patients of HBV genotype D usually have HBcrAg levels <3 log U/mL.17 Another marker to distinguish inactive carriers is HBV RNA that is a measurable marker of transcription of cccDNA.18

New drugs

A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors.19 Bulevertide binds to sodium taurocholate co-transporting polypeptide (NTCP), the uptake cell membrane transporter that allows HBV entrance into the hepatocyte. The drug has been recently approved in Europe as a treatment for viremic patients with hepatitis delta.20 The drug is undergoing phase III studies where monotherapy or in combination with interferon are investigated in patients with hepatitis B. The advances in hepatitis B therapeutics will influence the management guidelines in future.



References

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11. Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, et al. DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B. Antivir Ther. 2018;23(8):677-685. doi:10.3851/IMP3256

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14. Papatheodoridi M, Papatheodoridis G. Can we stop nucleoside analogues before HBsAg loss? J Viral Hepat. 2019;26(8):936-941. doi:10.1111/jvh.13091

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19. Soriano V, Barreiro P, Cachay E, Kottilil S, Fernandez-Montero JV, de Mendoza C. Advances in hepatitis B therapeutics. Ther Adv Infect Dis. 2020;7:2049936120965027. doi:10.1177/2049936120965027

20. Kang C, Syed YY. Bulevirtide: First Approval. Drugs. 2020;80(15):1601-1605. doi:10.1007/s40265-020-01400-1

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