Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease
Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease
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DOI：
10.1053/j.gastro.2015.05.010
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发表时间：
2015-09-01
期刊：
影响因子：
29.4
通讯作者：
Afdhal, Nezam
中科院分区：
文献类型：
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作者：
Charlton, Michael;Everson, Gregory T.;Afdhal, Nezam
背景与目的：对于晚期肝病患者的慢性丙型肝炎病毒（HCV）感染没有有效和安全的治疗方法。方法：在这项2期开放标签研究中，我们评估了NS 5A抑制剂ledipasvir、核苷酸聚合酶抑制剂sofosbuvir和利巴韦林对HCV基因型1或4感染患者的治疗。队列A招募了未接受肝移植的肝硬化和中度或重度肝损害患者。队列B招募了接受过肝移植的患者：无肝硬化患者;肝硬化伴轻度、中度或重度肝损害患者;纤维化淤胆性肝炎患者。患者被随机分配（1：1）接受12或24周的固定剂量复方片剂，含ledipasvir和sofosbuvir，每日一次，加利巴韦林。主要终点是治疗结束后12周的持续病毒学应答（SVR 12）。结果：我们纳入了337例患者，其中332例（99%）为HCV基因型1感染，5例（1%）为HCV基因型4感染。在队列A（非移植）中，86%-89%的患者实现了SVR 12。在队列B（移植受者）中，96%-98%的无肝硬化或代偿性肝硬化患者、85% - 88%的中度肝损害患者、60%-75%的重度肝损害患者以及所有6例纤维化淤胆性肝炎患者均达到了SVR 12。12周和24周组的反应率相似。13名患者（4%）因不良事件而提前停用ledipasvir和sofosbuvir联合治疗; 10名患者死亡，主要死于与肝功能失代偿相关的并发症。结论：ledipasvir，sofosbuvir和利巴韦林联合治疗12周，在晚期肝病患者中产生了较高的SVR 12发生率，包括肝移植前后失代偿期肝硬化患者。ClinTrials.gov：NCT01938430。
BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1: 1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85% - 88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.