乙肝治疗：第6部-哪类人应该治疗？

StephenW

哪类人应该治疗？

多种安全有效药品的使用已经拓展了乙肝病人治疗的适用症。这样，问题不再是哪些人应该治疗，而变成了——由于慢性乙肝感染者病情变化不定——应该什么时候开始治疗？开始或延期治疗的决定应该综合考虑肝脏疾病的活动情况及所处的阶段，评估期内HBV的复制情况和预测因治疗风险（不良反应，耐药和花费）发展为肝硬化和肝癌的风险和自然康复的可能性。美国肝病研究协会,欧洲肝脏研究协会，亚太肝脏研究协会和美国国立卫生研究院共识发展会议共同发布了关于何时开始治疗的指南。[58–62]

明确用药适用情形

急性肝衰竭或代谢失偿性肝硬化

有生命危险的肝病病人，如急性肝衰竭或代谢失偿性肝硬化应该尽快用核苷酸类药开始治疗。虽然支持这种情况下治疗效果的证据不足，但是利大于弊。抗病毒治毒同时可以降低肝移植病人乙型肝炎复发的风险。已经表明核苷酸类药物可以稳定肝脏疾病病情，在一些病例中可以逆转肝衰竭，从而免去肝移植的必要。[63,64] 和历史对照相比病人幸存率提高。[63,64]

代偿性肝硬化

有严重肝纤维化或代偿性肝硬化及HBV DNA水平高的病也应开始治疗，原因是抗病毒治疗已经在一个随机，双盲的安慰剂对照实验中表明可以阻止病情恶化。
[65] 在这个试验中，651名e抗原阳性，且/或HBV DNA水平高(~150,000 iu/ ml)的桥接纤维化或肝硬化的病人被随机分配给拉米夫定或安慰剂。[65] 试验在32个月的中位期后终止，因为接受治疗的病人病情恶化率及患肝癌率明显低，与服用安慰剂的病人病情恶化(定义为Child-Turcotte-Pugh分数提高大于2分,肝癌, 肾功能不全,静脉曲张破裂出血,自发性细菌腹膜炎及与肝脏相关的死亡) 率情况对比为(7.8% vs 17.7%,P = 0.001)，两者患肝癌的概率相比较 (3.9% versus 7.5%, P = 0.047)。虽然这个试验中的病人HBV DNA数量非常高，目前还是建议失代偿性肝硬化者在病毒数超过2000IU/ml时开始治疗，因为研究表明在病毒数超过10,000 copies/ml (也就是, ~2,000IU/ml)时患肝硬化和肝癌的风险增加。[9,10]

接受免疫抑制治疗的病人

建议因其它病症即将接受癌症化疗或免疫抑制治疗，表面抗原阳性的病人进行预防性抗病毒治疗以阻止HBV病毒活动重启。[58,60,66] 对14个研究的回顾发现在化疗或免疫抑制治疗之前或开始初期进行抗病毒治疗，HBV活动重启及引致HBV相关肝炎，肝衰竭，和死亡的机率下降80%-100%。[67]有既往感染感染乙肝病毒血清学依据（核心抗体阳性，表面抗体阴性或阳性）其HBV复制活动也可能重新启动但和表面抗原阳性的病人相比其机率要小，不明确是否需要预防性抗病毒治疗。

考虑治疗的情形

因为慢性乙肝感染者病程波动起伏，对补偿性肝硬化前期的病人作出何时开始治疗的决定非常困难。总的来说，HBV DNA水平持续处于高位，肝病处于活动期的病人应接受治疗。其它因素，如病人年龄，e抗原状况，家族肝癌史，职业要求（职业暴露的保健服务工作人员），家庭计划(生育年龄的妇女考虑不久怀孕)及病人的偏好可能影响做出开始或推迟治疗的决定。

e抗原阳性的慢性肝炎

e抗原阳性的病人谷丙转氨酶持续超过正常上限两倍或肝组织中度或重度发炎再或者肝纤维化严重时应考虑接受治疗。黄疸或乙肝炎症重度发作(即,凝血障碍或胆红素水平升高)应立即开始治疗。监测3-6个月其余病人的情况，只对e抗原没有自然转换的病人进行治疗。由于HBV DNA数量多或e抗原阳性与不良的医疗结果有极大关联，e抗原阳性的病人及40岁以上HBV DNA数量多(不论谷丙转氨酶正常与否)的病人应进行治疗。研究建议HBVDNA数量高的携带者母亲在孕期的第二或第三个月进行预防性抗病毒治疗可能会起到减少母婴传播风险的作用，且婴儿应注射免疫球蛋白及乙肝疫苗；然而，何时开始及何时可以停止抗病毒治疗还没有确定。[68,69]

E抗原阴性的慢性肝炎

E抗原阴性的慢性肝炎病人应考虑治疗。病情持续自然减轻的情况较少，没有设置预处理观察期。

.

哪种情况可以延迟治疗

一些病人可以延迟治疗，但这些病人应继续监测，一旦进行病毒复制期或肝病发作应立刻接受治疗。

免疫耐受期

E抗原阳性的年轻(40岁以下)病人正处于免疫耐受期，可以延迟治疗。这些病人肝活检通常没有肝纤维化或肝纤维化程度很小且后续10年的跟踪表明预后良好。[3]另外一个延迟治疗的原因是这些治疗引起e抗原转换的可能性很小。另一个原因是随时间推移，这些病人e抗原会自然转换。这些病人应持续监测，以确保如果e抗原没有自然转阴可以及时开始治疗。

非活动携带期

非活动的携带者可以延迟治疗;然而，非活动状态应该在一年内HBV DNA和谷丙转氨酶水平检查3到4次才能确认。

StephenW

Who should be treated?

The availability of multiple safe and efficacious drugs has expanded the indications for therapy in patients with hepatitis B. Thus, the question is no longer who should be treated but rather—owing to the fluctuating course of chronic HBV infection—when should treatment be initiated? The decision to start or to defer treatment should balance the activity and stage of liver disease, HBV replication status at the time of
assessment and the predicted risk of cirrhosis and HCC in the foreseeable future with the risks of treatment (adverse effects, drug resistance and costs) and the likelihood of spontaneous remission. Guidelines on when to start treatment have been developed by the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Asian Pacific Association for the Study of Liver and an NIH Consensus Development Conference.[58–62]

Situations in which treatment is clearly indicated

Acute liver failure or decompensated cirrhosis
In patients who have life-threatening liver disease, such as acute liver failure or decompensated cirrhosis, treatment with nucelos(t)ide analogues should be initiated as soon as possible. Although evidence supporting a benefit of treatment in these conditions is scanty, there is much to gain and very little to lose. Antiviral treatment also reduces the risk of recurrent hepatitis B should these patients require liver transplantation. Nucleos(t)ide analogue treatment has been shown to stabilize liver disease and in some cases reverse liver failure, allowing patients to be removed from the transplant waiting list.[63,64] Survival is also improved compared with historical controls.[63,64]

Compensated cirrhosis
Treatment should also be initiated in patients who have advanced fibrosis or compensated cirrhosis and high serum HBV DNA levels, because antiviral therapy has been shown to prevent disease progression in a prospective, randomized, double-blind, placebo-controlled trial.65 In this trial, 651 patients who were HBeAg positive and/or had high serum HBV DNA levels (~150,000 IU/ml) with
bridging fibrosis or cirrhosis were randomly allocated to receive lamivudine or placebo.65 This trial was terminated after a median duration of 32 months because treated patients had significantly lower rates of disease progression (defined as an increase in Child–Turcotte–Pugh score by ≥2 points, HCC, renal insufficiency, bleeding varices, spontaneous bacterial peritonitis and liver-related death) (7.8% versus 17.7%, P = 0.001) and HCC (3.9% versus 7.5%, P = 0.047) compared with patients who received placebo. Although patients in this trial had very high serum HBV DNA levels, the current recommendation for compensated cirrhosis is to initiate treatment in those who have serum HBV DNA levels >2,000 IU/ml, because studies have demonstrated that the risk of cirrhosis and HCC increases with serum HBV DNA levels >10,000 copies/ml (that is, ~2,000 IU/ml).[9,10]

Patients receiving immunosuppressive therapy
Prophylactic antiviral therapy is recommended for HBsAg-positive persons who will be receiving cancer chemotherapy or immunosuppressive therapy for other medical conditions to prevent reactivation of HBV replication.[58,60,66] A review of 14 studies found that antiviral therapy initiated before or at the onset of chemotherapy or immunosuppressive therapy reduced the incidence of HBV reactivation, HBV-related hepatitis, HBV-related liver failure, and HBV-related death by 80–100%.[67] Reactivation of HBV replication can also occur in patients who have serologic evidence of past HBV infection (presence of hepatitis B core antibody with or without anti-HBs) but the incidence is lower compared with patients who are HBsAg positive, and the need for prophylactic antiviral therapy is unclear.

Situations in which treatment should be considered

The decision regarding when to start treatment in patients who have compensated precirrhotic liver disease is complex because of the fluctuating course of chronic HBV infection. In general, patients who have persistently high serum HBV DNA levels and active liver disease should be treated. Other factors such as patient age, HBeAg status, family history of HCC, occupational requirements (health-care workers engaged in exposure-prone procedures), family planning (women of reproductive age contemplating pregnancy in the near future) and patient preference may influence the decision to start or to defer treatment.

HBeAg-positive chronic hepatitis
HBeAg-positive patients who have ALT levels persistently more than two times the upper limit of normal or histologic evidence of moderate or severe inflammation or advanced fibrosis should be considered for treatment. Patients who are jaundiced or who present with a severe flare of hepatitis B (that is, with coagulopathy or an increase in bilirubin levels) should begin treatment immediately. The remaining patients should be monitored for 3–6 months and treatment initiated only in those who fail to achieve spontaneous HBeAg seroconversion. Owing to
the strong association between adverse outcomes and high serum HBV DNA levels or the presence of HBeAg, patients who remain HBeAg positive, as well as those who have high serum HBV DNA levels beyond the age of 40, regardless of ALT level, should be considered for treatment. Studies suggest that there may be a role for antiviral prophylaxis starting in the second or third trimester of pregnancy in carrier mothers who have high serum HBV DNA levels to further reduce the risk of maternal–infant transmission in babies who will be receiving hepatitis B immunoglobulin and HBV vaccine; however, when antiviral therapy should be started and when it can be stopped has not been established.[68,69]

HBeAg-negative chronic hepatitis
Patients who have HBeAg-negative chronic hepatitis should be considered for treatment. Given that sustained spontaneous remission is rare, a period of pretreatment observation is not necessary.

Situations in which treatment may be deferred.

Treatment may be deferred in some patients but these patients should continue to be monitored so that treatment can be initiated at a later stage if HBV replication or liver disease becomes more active.

Immune tolerant phase
Treatment may be deferred in young (<40 years) HBeAg-positive patients who are in the immune tolerant phase. These patients generally have no or minimal fibrosis on liver biopsy and have a favorable prognosis during follow-up of up to 10 years.[3] Another reason for deferring treatment in these patients is the low likelihood of treatment-related HBeAg seroconversion. A third reason for deferring treatment is that some of these patients will undergo spontaneous HBeAg seroconversion with time. Continued monitoring of these patients allows timely initiation of treatment if they fail to undergo spontaneous HBeAg seroconversion.

Inactive carrier phase
Treatment may be deferred in inactive carriers; however, determination of inactivity should only be made after the patients have been observed for at least 1 year with HBV DNA and ALT levels tested on three or four occasions.

bjjww

author? which journal?

StephenW

bjjww 发表于 2011-5-9 22:52
author? which journal?

The authors are Hellan Kwon and Anna Lok. Professor Lok is well known internationally. The article was published a few days ago in  Nat. Rev. Gastroenterol. Hepatol. 8, 275–284 (2011).

bjjww

回复 StephenW 的帖子

many thanks

aiduoduo

顶起，大家来学习！

anny8527

妈的 我被庸医拉上贼船了，我才30多就叫我抗上了，虽然当时很重，转安酶1700多，胆红素质200多，肝功能各项指标都不正常，但那应该是免疫系统识别期，哎  上了贼船了。妈的我要杀了那家伙

StephenW

anny8527 发表于 2011-5-16 10:01
妈的 我被庸医拉上贼船了，我才30多就叫我抗上了，虽然当时很重，转安酶1700多，胆红素质200多，肝功能各项 ...

不要太生气.每个人的情况是不同的, 在书本中提到的案件只是一般情况下，可能并不适用于每个人。然而，你知道的越多，你可以更多与你的医生讨论.

zhcx2000

anny8527 发表于 2011-5-16 10:01
妈的 我被庸医拉上贼船了，我才30多就叫我抗上了，虽然当时很重，转安酶1700多，胆红素质200多，肝功能各项 ...

你抗病毒没错的，转氨酶这么高，时间长了功损严重。

雁过留声

免疫耐受期

E抗原阳性的年轻(40岁以下)病人正处于免疫耐受期，可以延迟治疗。这些病人肝活检通常没有肝纤维化或肝纤维化程度很小且后续10年的跟踪表明预后良好。[3]另外一个延迟治疗的原因是这些治疗引起e抗原转换的可能性很小。另一个原因是随时间推移，这些病人e抗原会自然转换。这些病人应持续监测，以确保如果e抗原没有自然转阴可以及时开始治疗。


这段很给力！！！
事实上很多战友在经历ＡＬＴ升高（有的甚至轻微偏高），实现了ＤＮＡ自然阴转，走向了肝功正常，实现了血清转换ＤＮＡ查不到的小三阳。
首次出现ＡＬＴ升高不要急于降酶或抗病毒，应该密切监测生化影像，是否进行抗病毒是由肝脏病理决定，ＡＬＴ和ＤＮＡ只是辅助参考性数据。