乙肝治疗：第5部-核苷（酸）类似物

StephenW

核苷（酸）类似物

已批准的五个核苷酸类似物可以分为三组：L型核苷(包括拉米夫定和替比夫定); 嘌呤类开环核苷磷化物(包括阿德福韦酯和替诺福韦酯); 脱氧鸟苷类(包括恩替卡韦)。乙肝病毒一旦进入肝细胞核，就会转变为一个叫做共价闭合环状DNA(cccDNA) 的完整双链DNA。cccDNA 承担前基因组RNA和信使RNA 转录的模板。前基因组RNA在肝细胞质中逆转录为HBV DNA。乙肝病毒聚合酶分为几个区间; POL/RT区间起逆转录酶和DNA聚合酶的作用(图表2) 。目前已批准的核苷酸类药主要作用是阻止前基因组RNA 逆转录到
HBV DNA的第一条链。这些药物不能直接作用于cccDNA；停药后，病毒数常常反弹。

e抗原阳性的慢性肝炎

服用核苷酸类药物一年检测不到血清中HBV DNA的机率很高(21-76%),谷丙转氨酶正常(41-77%),且肝组织学改善(49-74%), 但只有12-22%的病人e抗原转阴同时只有 0-3%的病人表面抗原消失(表格1). [29-34]确认e抗原转阴后继持治疗12个月以巩固应答效果并减少e扩原再次出现的可能。[35]延长核苷酸类药治疗时间超过1年，服药5年后可以增加e抗原转阴率至40-50%但表面抗原下降率仍低于10%。[36-40] 对病人进行超过3年的跟踪，肝活组织检查表明肝脏炎症和肝纤维化减轻，证明抗病毒治疗可以使肝损伤逆向变化。[41-43]

e抗原阴性的慢性肝炎

服用核苷酸类药物一年检测不出HBV DNA的概率非常高(51–93%), 谷丙转氨酶正常(62–78%),且肝组织学改善(60–72%), 但表面抗原转阴率不到1%(表格1)。[33,34,44–46]停药后几乎所有病人会出现反弹。延续使用阿德福韦酯或替诺福韦酯4-5年后，保持病毒抑制的概率仍很高(67–86%)，但表面抗原下降的概率仍旧很低（0-5%）。[42，47]

抗病毒药物的耐药性

抗病毒药物的耐药是限制核苷酸类药物长期成功的重要因素。[48]耐药出现的初期表现是病毒学突破，表现为HBV DNA升高数量超过病毒数最少时的一个对数,或先前检测不到HBV DNA现在可以重新检测到。病毒学突破可能随着生化突破(先前正常的谷丙转氨酶水平重新升高)出现，若症状出现初期未及时抢救治疗会导致肝炎和肝代谢失偿。

如图表2 所示 HBV聚合酶的识别标志突变与已批准核苷酸类药的耐药有关。[48]据报道五种核苷酸类药使用1年耐药发生率自用药一年的0-25%到用药五年的1-70%

之间变化。[36,39,40,42,47,49]一些突变引起一止一种药的耐药; 例如，蛋氨酸到缬氨酸或异亮氨酸替代物(rtM204v/i)的突变,和拉米夫定耐药有关, 同时与替比夫定耐药

有关且会降低恩替卡韦的敏感性。[50]这个发现解释了先前治疗失败再次用药时耐药性高的原因。(表格3).[49,51] 因为持续单一药物治疗会导致多种耐药盒，治疗初期

选用高基因障碍（耐药倾向低）的药物很重要。[52]

预测应答

E抗原阳性的病人中, 治疗前谷丙转氨酶水平处于高位的有高预测性。[22，53]对于e抗原阴性的病人，没有一致的治疗应答预测。核苷酸类药的病毒学应答预测在所要主要的HBV基因类型中都相似，这一点和干扰素不同。[54]

不良反应

核苷酸类药物对乙型肝炎的耐受性非常好。据道到阿德福韦酯和替诺福韦酯有潜在肾毒性,其表现为连续用药3-5年后血清中肌酸酐水平升高3%，伴发肾小管功能障碍，包括范科尼综合征。[37，40，42，47，55 ]另有报道恩替卡韦会降低骨矿物质密度（尤其是儿童）。[56 ]替比夫定（尤其是与聚乙二醇干扰素合用时）可能导致肌肉病变和周围神经变。[39]在一个病例系列中, 服用恩替卡韦的病人中有严重肝功能障碍者可能会引起乳酸性酸中毒。[57]这些数据表明虽然短期使用核苷酸类药物安全性很好，但长期服用时安全性并不行。

使用剂量

用于乙肝治疗的核苷酸类药口服使用，一天一次，一次一片。有肾功能障碍的病人服用核类药时应调整剂量。

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StephenW

StephenW

StephenW

Nucleos(t)ide analogues

The five approved nucleos(t)ide analogues can be divided into three groups: l‑nucleosides (including lamivudine and telbivudine); acyclic nucleoside phosphonates
(including adefovir dipivoxil and tenofovir disoproxil); and deoxyguanosine analogues (including entecavir). Upon entry into the hepatocyte nucleus, HBV DNA is transformed into a fully double-stranded DNA known as covalently closed circular DNA (cccDNA). This cccDNA serves as the template for transcription of the pregenomic RNA and messenger RNAs. The pregenomic RNA is reverse transcribed into HBV DNA in the hepatocyte cytoplasm. The HBV polymerase is divided into several domains; the POL/RT domain functions as a reverse transcriptase as well as a DNA polymerase. Currently approved nucleos(t)ide analogues act primarily by inhibiting the reverse transcription of the pregenomic HBV RNA to the first strand of HBV DNA. These agents do not have any direct inhibitory effect on cccDNA; viral relapse is common, therefore, when treatment is stopped.

HBeAg-positive chronic hepatitis

A 1‑year course of treatment with nucleos(t)ide analogues results in high rates of undetectable serum HBV DNA (21–76%), normalization of ALT levels (41–77%), and histologic improvement (49–74%), but only 12–22% of patients achieve HBeAg seroconversion and only 0–3% lose HBsAg (Table 1).[29–34] Continuing treatment for 12 months after confirmation of HBeAg seroconversion consolidates the response and reduces the likelihood of HBeAg seroreversion.35 Extending the duration of nucleos(t)ide treatment beyond 1 year results in increasing rates of HBeAg seroconversion to 40–50% after 5 years of treatment but rates of HBsAg loss remain below 10%.36–40 Follow-up liver biopsies performed in patients who had maintained viral suppression for ≥3 years demonstrated a reduction in both inflammation and fibrosis, indicating that antiviral therapy can reverse liver damage.[41–43]

HBeAg-negative chronic hepatitis

A 1‑year course of treatment with nucleos(t)ide analogues results in very high rates of undetectable serum HBV DNA (51–93%), normalization of ALT levels (62–78%), and histologic improvement (60–72%), but <1% lose HBsAg (Table 1).[33,34,44–46] Viral relapse occurs in almost all patients when treatment is discontinued. Extending treatment with adefovir dipivoxil or tenofovir disoproxil to 4–5 years results in a high rate of maintained viral suppression (67–86%), but the rate of HBsAg loss remains low (0–5%).[42,47]

Antiviral drug resistance

Antiviral drug resistance is a major limitation to the long-term success of nucleos(t)ide analogue treatment.48 Emergence of antiviral resistance is initially manifested as virologic breakthrough, which is defined as an increase in serum HBV DNA levels by >1 log from nadir, or the redetection of HBV DNA after it had become undetectable. Virologic breakthrough may be followed by biochemical breakthrough (increased ALT levels in a patient who previously had normalized ALT levels), hepatitis flares and hepatic decompensation if salvage therapy is not initiated. Signature mutations in HBV polymerase that are associated with resistance to the approved nucleos(t)ide analogues are shown in Figure 2.[48] The reported incidence of genotypic resistance to the five approved nucleos(t)ide
analogues varies from 0–25% at 1 year to 1–70% at 5 years (Table 2). [36,39,40,42,47,49] Some mutations confer resistance to more than one drug; for example, a methionine to valine or isoleucine substitution (rtM204V/I), which is associated with lamivudine resistance, also confers resistance to telbivudine and decreases susceptibility to entecavir.[50] This finding explains the high rate of drug resistance in patients with previous treatment failure.[49,51] It is important to initiate treatment with a drug that has a high genetic barrier to resistance (low potential for drug resistance) because sequential monotherapy may result in the selection of multidrug resistance mutations.[52]

Predictors of response

Among HBeAg-positive patients, high pretreatment levels of serum ALT are the strongest predictor of treatment response.22,53 For HBeAg-negative patients, there is no consistent predictor of treatment response. Unlike IFN treatment, virologic response to nucleos(t)ide analogues is similar across all the major HBV genotypes.[54]

Adverse effects

Nucleos(t)ide analogues for hepatitis B are very well tolerated. Adefovir dipivoxil and tenofovir disoproxil are reportedly associated with nephrotoxicity, which manifests as an increase in serum creatinine levels in 3% of patients after 3–5 years of continuous treatment, as well as renal tubular dysfunction, including Fanconi syndrome.[37,40,42,47,55] Tenofovir disoproxil has also been reported to decrease bone mineral density, particularly in children.[56] Telbivudine may cause myopathy and peripheral neuropathy, especially when used in combination with PEG-IFN.39 In one case series, entecavir was shown to be associated with lactic acidosis in patients who had severe liver dysfunction.[57] These data indicate that although nucleos(t)ide analogues for hepatitis B have excellent short-term safety, the long-term safety of these drugs has not been established.

Dose regimen

Nucleos(t)ide analogues for hepatitis B are administered orally as a single pill once a day. Doses of all the approved nucleos(t)ide analogues should be adjusted in patients who have impaired renal function.

antihbv2

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682256

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