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First-Line Treatment
Approved medications for chronic HBV infection include interferon (IFN), either standard or pegylated IFN (PEG-IFN), and NUCs, lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir disoproxil fumarate. Rates of response and resistance to these medications are summarized in Table 2.16
Interferon/Pegylated-Interferon
IFN has both antiviral and immunomodulatory activity, which may lead to a higher rate of HBeAg and HBsAg loss and more durable viral suppression. Phase 3 clinical trials showed that 1-year treatment with pegylated-interferon (PEG-IFN) with or without lamivudine in HBeAg-positive patients resulted in 29% to 32% HBeAg seroconversion and 3% to 7% HBsAg loss 24 weeks after completion of treatment.17, 18 In one study, follow-up evaluation of patients for 3.5 years after completion of treatment found that HBeAg loss was durable in 81% and HBsAg loss occurred in 30% (58% for genotype A and 11% for genotype non-A) of patients.19 Phase 3 clinical trials showed that 1-year treatment of PEG-IFN with or without lamivudine in HBeAg-negative patients resulted in a sustained response, defined as normalization of ALT level, suppression of HBV DNA levels to 10,000 IU/mL or less in approximately 25% of patients, and HBsAg loss in 9% at 3 years after completion of treatment.20
IFN is administered parenterally and has many side effects. High serum ALT levels, low viral load, HBV genotype A and B, and high histologic activity index are pretreatment predictors of IFN/PEG-IFN response in HBeAg-positive patients.21 Predictive factors for response in HBeAg-negative patients have not been defined clearly. On-treatment ALT flares and HBsAg decreases and interleukin-28B polymorphisms also have been reported to be associated with IFN/PEG-IFN response.18, 22, 23, 24
一线治疗
批准的药物用于治疗慢性HBV感染包括干扰素(IFN) ,无论是标准的或聚乙二醇化干扰素( PEG-IFN )和NUCs ,拉米夫定,阿德福韦酯,替比夫定,恩替卡韦,和富马酸替诺福韦酯。响应性和耐这些药物的速率汇总于表2.16
干扰素/聚乙二醇干扰素
干扰素具有抗病毒和免疫调节活性,这可能导致更高的速率HBeAg和HBsAg消失和更持久的病毒抑制。第3阶段临床试验表明,与聚乙二醇干扰素( PEG-IFN )有或没有拉米夫定治疗HBeAg阳性患者1年的治疗导致29 %至32 %的HBeAg血清转换和3 %至7 %的HBsAg完成税后亏损24周treatment.17 , 18在一项研究中,患者接受治疗完成后3.5年后续评估发现, 81%的HBeAg消失是耐用, HBsAg消失发生在30 % ( 58 %为基因型A和11 %的非基因型- A的patients.19 3期临床试验)表明, 1年的治疗PEG-IFN的有或无拉米夫定治疗HBeAg阴性患者造成了持续的反应,定义为ALT正常化水平,抑制HBV DNA水平至10,000国际单位/毫升或更少的患者约25%,而HBsAg消失在9 % ,3年treatment.20完成后
干扰素是胃肠外给药,并有许多副作用。高血清ALT水平,病毒载量低, HBV基因型A和B ,以及高组织学活动指数是HBeAg阳性patients.21预测因素干扰素/ PEG-IFN应答的响应中HBeAg阴性患者治疗前预测尚未确定清楚了。对治疗ALT升高和降低乙肝表面抗原和白细胞介素-28B基因多态性也已被报道用IFN / PEG-IFN response.18 , 22 , 23 , 24相关的
Nucleos(t)ide Analogues
NUCs have become the mainstay of CHB treatment because they can be administered orally and have potent antiviral activity and very few side effects. A major drawback with earlier NUCs was the high rate of antiviral drug resistance; however, the new NUCs, entecavir and tenofovir, have high barriers to resistance, with rates of antiviral drug resistance reported to be 1.2% and 0% after 5 years of treatment, respectively, in phase 3 trials of NUC-naive patients.9, 20, 25, 26 The risk of entecavir resistance is much higher, 51% after 5 years of treatment, in patients with lamivudine-resistant HBV.27 Continued treatment with entecavir or tenofovir for up to 5 years resulted in undetectable serum HBV DNA levels in 94% to 98% of patients, HBeAg seroconversion in 40% to 41% of HBeAg-positive patients, and HBsAg loss in 3% to 10%.26, 28 Long-term viral suppression has been shown to reverse fibrosis and cirrhosis.9, 28
High pretreatment ALT level is the most important predictor of response to NUC treatment in HBeAg-positive patients.29 Predictors of response to NUC have not been identified for HBeAg-negative patients. Contrary to IFN, HBV genotype is not predictive of response to NUC, and NUC treatment results in a minimal decrease in HBsAg levels.
Resistance to lamivudine or telbivudine (M204V/I) increases the risk of resistance to entecavir, and resistance to adefovir (N236T) decreases susceptibility to tenofovir. To date, there has been no confirmed case of genotypic resistance to tenofovir in patients with HBV monoinfection. Combination of 2 NUCs with no cross-resistance have been proposed to prevent the development of drug resistance; however, the need for combination therapy is doubtful given the low rate of resistance to entecavir or tenofovir monotherapy. Furthermore, although combination of 2 NUCs can accelerate viral suppression in patients with high viremia,30 there is no evidence that combination therapy will result in incremental clinical benefit.
Approved NUCs for HBV are generally safe. Mitochondrial toxicity is a potential side effect of NUCs but is very rare. Myopathy and neuropathy have been reported in patients treated with telbivudine,31 lactic acidosis has been reported in patients with severely impaired liver function treated with entecavir,32 and nephrotoxicity and renal tubular dysfunction have been reported in patients receiving adefovir or tenofovir.33
核苷(酸)类似物
NUCs已成为慢性乙型肝炎治疗的中流砥柱,因为它们可以口服给药,并有强大的抗病毒活性,副作用很少。与早期NUCs一个主要缺点是抗病毒耐药率很高,但新的NUCs ,恩替卡韦和替诺福韦,具有高壁垒性,有报告了5年的治疗后为1.2 %和0%的抗病毒药物耐药率,分别在相NUC-天真patients.9 , 20 , 25 , 26 3试验恩替卡韦耐药的风险要高得多,后51 %5年的治疗,患者恩替卡韦与拉米夫定耐药HBV.27继续治疗或替诺福韦为长达5年导致94 %至98 %的患者检测不到血清HBV DNA水平, HBeAg血清转换率在40 %至HBeAg阳性患者的41 % ,而HBsAg消失在3 %至10 % .26 28长期抑制病毒已显示逆转纤维化和cirrhosis.9 , 28
治疗前高ALT水平是应对国统会处理响应NUC的HBeAg阳性patients.29预测的最重要的预测还没有被确定为HBeAg阴性患者。相反,干扰素,乙肝病毒基因型不能预测针对国统会,并NUC治疗结果在HBsAg水平的最小跌幅。
耐拉米夫定或替比夫定( M204V / I)增加抗恩替卡韦的风险,和耐阿德福韦( N236T )降低易感性替诺福韦。到目前为止,已经替诺福韦基因型耐药患者HBV单一感染没有确诊病例。 2 NUCs无交叉耐药性组合已经提出防止产生耐药性的发展,但是,需要联合治疗是值得怀疑的给予耐恩替卡韦或替诺福韦单药治疗率低。此外,尽管2 NUCs组合能加速病毒抑制的患者具有高病毒血症, 30 ,没有证据表明,联合治疗将导致增加的临床益处。
批准NUCs乙肝一般是安全的。线粒体毒性是NUCs的一个潜在的副作用,但非常罕见。肌病和神经病变已报道在替比夫定治疗的患者中, 31乳酸性酸中毒已报道的患者恩替卡韦治疗肝功能严重受损, 32和肾毒性和肾小管功能障碍已报道在接受阿德福韦或tenofovir.33患者
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