毒理性
在大规模随机对照试验中，使用Zepatier治疗的患者的血清转氨酶升高超过正常上限（ULN）的5倍的发生率为1%，而在安慰剂接受者中则很少见。这些升高通常无症状且短暂，经常在治疗的前4周后出现，并在剂量调整或未经调整的情况下解决，很少需要提前终止。在某些情况下，ALT水平升高超过正常上限的10倍，但这些升高并未伴随症状或黄疸，并且总是自限性的。在许多预注册试验中，Zepatier并未与临床上明显的肝损伤病例相关联。
然而，有两种形式的肝损伤与用于治疗慢性丙型肝炎的直接作用抗病毒药物相关联，这些反应似乎与所有治疗方案都有关。第一种是丙型肝炎相关肝硬化的急性失代偿。肝损伤通常在开始抗病毒治疗后的2到6周内出现，但可能会在以后甚至治疗停止后发生。损伤表现为黄疸加重和肝衰竭的迹象，如腹水或肝性脑病，血清转氨酶水平通常很少有或没有变化。早期可能会出现乳酸酸中毒。病程变化不定，但需要立即停止治疗，尽管成功抑制了HCV RNA水平。某些情况下已导致死亡或需要紧急肝移植。因此，接受像Zepatier这样的强效直接作用药物进行抗病毒治疗的肝硬化患者应受到密切监测，尤其是在治疗的前几周。这种综合征尚未明确与使用 grazoprevir 和 elbasvir 的治疗相关联，但该方案尚未在因丙型肝炎导致的晚期肝硬化患者中进行评估。
第二种治疗慢性丙型肝炎的并发症是乙型肝炎的再激活。这最常见于血清中存在HBsAg的患者，但在没有HBsAg的抗HBc阳性受试者中也有罕见发生。在治疗丙型肝炎期间乙型肝炎再激活的原因尚不清楚，但可能与在HCV复制期间抑制HBV复制有关。因此，将要接受抗病毒治疗的丙型肝炎患者应筛查HBsAg和抗HBc。HBsAg阳性的患者最好通过同时使用对HBV有效的抗病毒药物（如恩替卡韦或替诺福韦）进行治疗。没有HBsAg的抗HBc阳性受试者很少经历再激活，可以通过在治疗期间密切监测HBV DNA水平并在水平出现新发或显著升高时对HBV进行治疗来进行管理。乙型肝炎的再激活已在使用许多治疗方案中描述，尽管并未特别与grazoprevir和elbasvir相关。
可能性评分：E*（未证实但怀疑是临床上明显肝损伤的原因）。
In large randomized controlled trials, serum aminotransferase elevations more than 5 times the upper limit of normal (ULN) occurred in 1% of Zepatier treated patients, but were infrequent in placebo recipients. The elevations were generally asymptomatic and short-lived, often arising after the first 4 weeks of therapy and resolving with or without dose modification and only rarely requiring early discontinuation. In some instances, ALT levels rose above 10 times the upper limit of normal, but these elevations were not accompanied by symptoms or jaundice and were invariably self-limited. In the many preregistration trials, Zepatier was not associated with instances of clinically apparent liver injury.
However, two forms of liver injury have been associated with direct-acting antiviral agents used to treat chronic hepatitis C, and these reactions appear to occur with all regimens. The first is acute decompensation of HCV-related cirrhosis. The liver injury usually arises within 2 to 6 weeks of starting antiviral therapy, but can occur later and even after discontinuation. The injury is marked by worsening jaundice and appearance of signs of hepatic failure such as ascites or hepatic encephalopathy, often with little or no change in serum aminotransferase levels. Lactic acidosis may be present early. The course is variable but calls for prompt discontinuation of treatment despite successful suppression of HCV RNA levels. Some instances have led to death or need for emergency liver transplantation. For this reason, patients with cirrhosis undergoing antiviral therapy with potent direct acting agents, such as Zepatier, should be monitored carefully, particularly during the first few weeks of treatment. This syndrome has not been clearly linked to therapy with grazoprevir and elbasvir, but this regimen has not been evaluated in patients with advanced cirrhosis due to hepatitis C.
A second, liver complication of therapy of chronic hepatitis C is reactivation of hepatitis B. This occurs most frequently in patients who have HBsAg in serum but rare instances have arisen in subjects with anti-HBc without HBsAg. The cause of the reactivation of hepatitis B during antiviral therapy of hepatitis C is unknown, but may relate to the inhibition of HBV replication during HCV replication. For this reason, patients with hepatitis C who are to receive antiviral therapy should be screened for HBsAg and anti-HBc. Those with HBsAg are best managed by concurrent treatment with an antiviral agent active against HBV, such as entecavir or tenofovir. Subjects with anti-HBc without HBsAg rarely experience reactivation and can be managed by careful monitoring for HBV DNA levels during treatment and institution of therapy for HBV if levels appear de novo or rise significantly. Reactivation of hepatitis B has been described with many regimens, although not specifically with grazoprevir and elbasvir.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
来源:LiverTox
