Queen Mary University of London, The Liver Unit, Blizard Institute of Cellular and Molecular Science, Barts and The London School of Medicine, The Royal London Hospital, London, UK.
Drugs. 2010;70(2):147-65. doi: 10.2165/11531990-000000000-00000.
Chronic infection with hepatitis C virus (HCV) is a major healthcare problem, affecting an estimated 170 million people worldwide. Interferon-alpha has formed the basis of treatment regimens since the identification of HCV, either alone or in conjunction with the nucleoside analogue ribavirin. The relatively recent introduction of pegylated forms of interferon-alpha, with greater stability and in vivo activity, has substantially improved sustained virological response (SVR) rates compared with unmodified interferon-alpha, with SVR rates of 35-66% when used in conjunction with ribavirin in randomized controlled trials. Two pegylated interferon (peginterferon)-alpha molecules are commercially available for the treatment of chronic hepatitis C, and these differ in the size and nature of the covalently attached polyethylene glycol (PEG) moiety, with resulting differences in pharmacokinetics and in dosing regimens. Peginterferon-alpha-2b has a linear 12 kDa PEG chain covalently attached primarily to histidine-34 of interferon-alpha-2b via an unstable urethane bond that is subject to hydrolysis once injected, releasing native interferon-alpha-2b. The branched, 40 kDa PEG chain of peginterferon-alpha-2a is covalently attached via stable amide bonds to lysine residues of interferon-alpha-2a, and circulates as an intact molecule. Consequently, peginterferon-alpha-2a has a very restricted volume of distribution, longer half-life and reduced clearance compared with native interferon-alpha-2a, and can be given once weekly independently of bodyweight. Peginterferon-alpha-2b has a shorter half-life in serum than peginterferon-alpha-2a and requires bodyweight-based dosing. The majority of head-to-head randomized controlled trials, including the large, randomized IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial (n = 3070), demonstrated similar SVR rates for peginterferon-alpha-2a and peginterferon-alpha-2b (41% vs 39% in IDEAL), in combination with ribavirin; however, two randomized controlled trials (n = 431 and 320) demonstrated a statistically significant benefit for peginterferon-alpha-2a (66% vs 54%, and 69% vs 54%). Furthermore, two large retrospective studies and one prospective observational study in real-life settings have shown a significant benefit for peginterferon-alpha-2a versus peginterferon-alpha-2b, although SVR rates were generally lower than those seen in controlled trials. The use of interferon-alpha with or without ribavirin is frequently associated with a range of adverse effects, including influenza-like symptoms, haematological changes and neuropsychiatric disturbances, and this is true also of the peginterferons, with similar levels of adverse events, dose reduction and discontinuation from treatment. Peginterferon-alpha-2a and peginterferon-alpha-2b appear from comparative studies to be similarly tolerated, with few differences of clinical significance noted. Peginterferon plus ribavirin, as the standard of care for patients with chronic hepatitis C, may in the future form the basis of improved treatment regimens that include new, targeted anti-HCV agents to increase SVR rates even further.
慢性丙型肝炎病毒（HCV）感染是一个主要的医疗保健问题，全球估计有 1.7 亿人受到影响。自 HCV 被发现以来，干扰素-α一直是治疗方案的基础，无论是单独使用还是与核苷类似物利巴韦林联合使用。最近引入的聚乙二醇（PEG）化形式的干扰素-α，具有更高的稳定性和体内活性，与未修饰的干扰素-α相比，大大提高了持续病毒学应答（SVR）率，在随机对照试验中与利巴韦林联合使用时，SVR 率为 35-66%。有两种商业化的聚乙二醇干扰素（peginterferon）-α用于治疗慢性丙型肝炎，它们在共价连接的 PEG 部分的大小和性质上有所不同，导致药代动力学和剂量方案的差异。聚乙二醇干扰素-α-2b 具有线性 12 kDa PEG 链，主要通过不稳定的氨酯键共价连接到干扰素-α-2b 的组氨酸 34 上，一旦注射，该键就会水解，释放出天然的干扰素-α-2b。聚乙二醇干扰素-α-2a 的分支、40 kDa PEG 链通过稳定的酰胺键共价连接到干扰素-α-2a 的赖氨酸残基上，并作为完整的分子循环。因此，聚乙二醇干扰素-α-2a 的分布体积非常有限，半衰期较长，清除率降低，与天然干扰素-α-2a 相比，每周可单独给药一次，与体重无关。聚乙二醇干扰素-α-2b 在血清中的半衰期短于聚乙二醇干扰素-α-2a，需要根据体重进行给药。大多数头对头随机对照试验，包括大型随机 IDEAL（个体化剂量疗效与平坦剂量评估最佳聚乙二醇干扰素治疗）试验（n=3070），显示聚乙二醇干扰素-α-2a 和聚乙二醇干扰素-α-2b 联合利巴韦林的 SVR 率相似（IDEAL 中分别为 41%和 39%）；然而，两项随机对照试验（n=431 和 320）表明聚乙二醇干扰素-α-2a 具有统计学上的优势（66%比 54%，69%比 54%）。此外，两项大型回顾性研究和一项真实环境下的前瞻性观察性研究表明，聚乙二醇干扰素-α-2a 优于聚乙二醇干扰素-α-2b，尽管 SVR 率通常低于对照试验。干扰素-α联合或不联合利巴韦林的使用常伴有一系列不良反应，包括流感样症状、血液学改变和神经精神障碍，聚乙二醇干扰素也存在类似的不良反应，需要减少剂量和停药。从比较研究来看，聚乙二醇干扰素-α-2a 和聚乙二醇干扰素-α-2b 的耐受性似乎相似，只有少数具有临床意义的差异。聚乙二醇干扰素加利巴韦林作为慢性丙型肝炎患者的标准治疗方法，将来可能会成为改进治疗方案的基础，这些方案包括新的、靶向抗 HCV 药物，以进一步提高 SVR 率。
