乙肝治疗: 第4部-干扰素

StephenW

干扰素

干扰素兼具抗病毒和免疫调节作用。对用干扰素治疗的病人长期跟踪，结果表明治疗应答者发生代偿机能减退及患肝癌的概率降低并且总体寿命比无治疗应答者延长。[11-15] 聚乙二醇干扰素因只需一周注射一次而不是常规干扰素的一天一次或一周三次且治疗应答率更高，已经取代常规干扰素。

e抗原阳性的慢性肝炎应答情况

对e抗原阳性的病人治疗一年，治疗结束24周后进行评估，
使用聚乙二醇干扰素的患者e抗原转阴率接近30% （表格1）。

[16-18]附加使用拉米夫定使治疗期间HBV DNA水平下降率增大但不能增加e抗原转阴率。在一个试验中对病人聚乙二醇干扰素（不论是否伴有拉米夫定）治疗后，进行平均3.5年的跟踪发现37%的人e抗原消失且11%的人表面抗原消失(其中28%为a型基因感染，3%为非a型基因感染)。[19]

e抗原阴性的慢性肝炎应答情况

对e抗原阴性的患者用聚乙二醇干扰素治疗一年，治疗结束后24周对病人进行评估，HBV DNA转阴且谷丙转氨酶水平正常的概率为15%（表格1）。[20]

治疗期间同时使用拉米夫定使HBV DNA转阴率进一步增加但延期治疗不能增加病毒

学应答率。聚乙二醇干扰素(不论附加拉米夫定与否) 与只用拉米夫定在治疗完成3年后的情况分别进行比较，HBV DNA阴性人数分别为16% vs6%, 谷丙转氨酶水平正常人数分别为31% vs 18%,表面抗原下降的人数分别为8% vs 0%。[21]

应答预测

e抗原阳性的患者中，治疗前谷丙转氨酶水平升高,e抗原转阴的概率最大。[22 ]其他预测指标包括组织学活动指标高,DNA水平低，感染的乙肝病毒是a型或b型。[23，24]e抗原阴性的患者中，第12周时表面抗原滴度明显下降或滴度水平低可以预测产生持续病毒的概率大。[25，26]

不良反应

使用初期，干扰素常见的不良反应是类流感症。其它常见的

不良反应包括乏力，食欲不振，轻度脱发，易怒，骨髓功能

抑制，出现或加重自身免疫性疾病。

失代偿性肝硬化者禁用干扰素，因其有患脓毒症和加重肝

衰竭的风险。[27]因乙肝引起肝衰竭或慢性乙肝病情恶化的病

人不应该使用干扰素。然而有证据表明对谨慎重筛选选出的

补偿性肝硬化患者（化验结果表明肝脏合成功能正常且没有

门静脉高压症表现的）使用干扰素是安全的。[28]

使用剂量

聚乙二醇-α2a干扰素准许剂量为皮下注量每周180 μg，聚乙

二醇-α2b在许多国家准许用于慢性乙肝治疗但在美国不

被允许。聚乙二醇-α2b(依体重每周0.5–1.5 μg/kg)已经被用

于临床试验。

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StephenW

Interferon

IFN has both antiviral and immunomodulatory activity. Long-term follow-up of patients treated with conventional IFN therapy showed that responders had a decreased incidence of decompensation and HCC and improved overall survival compared with nonresponders.[11–15] PEG-IFN has superseded conventional IFN because it can be administered once a week instead of daily or three times a week and because it is associated with a higher rate of response.

Response in HBeAg-positive chronic hepatitis

A 1‑year course of PEG-IFN resulted in HBeAg seroconversion in approximately 30% of HBeAg-positive patients when assessed 24 weeks after completion of treatment (Table 1).[16–18] The addition of lamivudine led to a greater decrease in serum HBV DNA levels during treatment but did not increase the rate of HBeAg seroconversion. Follow-up of patients in one trial for a mean of 3.5 years after completion of PEG-IFN with or without lamivudine found that 37% had lost HBeAg and 11% had lost HBsAg (28% among those with genotype A infection and 3% among those with nongenotype A infection).[19]

Response in HBeAg-negative chronic hepatitis

A 1‑year course of PEG-IFN resulted in undetectable serum HBV DNA and normalization of ALT levels in 15% of HBeAg-negative patients when assessed 24 weeks after completion of treatment.20 Addition of lamivudine led to a greater decrease in serum HBV DNA levels during treatment but did not increase the rate of off-treatment virologic response. 3 years after completion of treatment, serum HBV DNA remained undetectable in 16% versus 6% of patients, ALT levels remained normal in 31% versus 18% of patients, and HBsAg loss occurred in 8% versus 0% of patients, of patients who received PEG-IFN with or without lamivudine versus lamivudine alone, respectively.[21]

Predictors of response

Among HBeAg-positive patients, the most reliable predictor of HBeAg seroconversion is increased levels of ALT prior to treatment.22 Other predictors include a high histologic activity index, low serum HBV DNA levels, and infections with HBV genotypes A or B.[23,24] Among HBeAg-negative patients, a more marked decline in the serum HBsAg titer or a lower HBsAg titer at week 12 seems to be associated with a higher rate of sustained virologic response.[25,26]

Adverse effects

The most common adverse effect of IFN is an initial flu-like illness. Other common adverse effects include fatigue, anorexia, a mild increase in hair loss, emotional lability, bone marrow suppression, and unmasking or exacerbation of autoimmune illnesses.
IFN is contraindicated in patients with decompensated cirrhosis because of the risk of sepsis and worsening liver failure.[27] IFN should also not be used in patients with HBV-related acute liver failure or severe exacerbations of chronic hepatitis B. IFN has, however, been shown to be safe in carefully selected patients who have compensated cirrhosis (those whose laboratory tests indicate normal hepatic synthetic function and who have no evidence of portal hypertension).[28]

Dose regimen

The approved dose of PEG-IFN-α2a is 180 μg weekly, administered subcutaneously. PEG-IFN-α2b is approved for the treatment of chronic hepatitis B in many countries but not in the US. Various doses of PEG-IFN-α2b (0.5–1.5 μg/kg body weight weekly) have been used in clinical trials.

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