在丙型肝炎病毒 1 型和 HIV 合并感染且伴有或不伴有肝硬化的 NS3/4A 蛋白酶抑制剂经治个体中，使用 ledipasvir/sofosbuvir 的疗效、安全性和患者报告结局（ANRS HC31 SOFTRIH 研究）。
Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).
机构信息
Internal Medicine Department, CHU de Nice, Hôpital Archet 1, Nice, France.
Pharmacology Department, CHU Rennes, Rennes, France.
出版信息
HIV Med. 2018 Mar;19(3):227-237. doi: 10.1111/hiv.12571. Epub 2017 Dec 7.
OBJECTIVES
Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis.
METHODS
We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes.
RESULTS
Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified.
CONCLUSIONS
LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.
目的
评估固定剂量组合 ledipasvir（LDV）/索磷布韦（SOF）在合并感染 HIV-1 和丙型肝炎病毒（HCV）的患者中的疗效和安全性的研究主要包括未经治疗且无肝硬化的初治患者。我们旨在评估该联合用药在有或无肝硬化的经验丰富的治疗患者中的疗效和安全性。
方法
我们进行了一项多中心、开放性、双臂、非随机研究，纳入了合并感染 HIV-1 和 HCV 基因型 1 且有或无肝硬化的患者，这些患者的抗逆转录病毒治疗方案已实现良好的病毒抑制。所有患者均先用第一代 NS3/4A 蛋白酶抑制剂（PI）加聚乙二醇干扰素/利巴韦林预处理。患者接受 LDV/SOF 固定剂量联合治疗 12 周，如果存在肝硬化则治疗 24 周。主要终点是治疗结束后 12 周的持续病毒学应答（SVR）。次要终点包括安全性、药代动力学和患者报告的结果。
结果
在纳入的 68 例患者中，39.7%有肝硬化。65 例患者（95.6%；95%置信区间：87.6-99.1%；P < 0.0001）获得了 SVR，且有和无肝硬化的患者 SVR 率相似。耐受性良好，主要为 1 级或 2 级不良事件。在患者报告的结果中，只有治疗结束时的疲劳与基线相比显著下降[比值比（OR）：0.36；95%置信区间：0.14-0.96；P = 0.04]。第 4 周时替诺福韦的平均血浆浓度-时间曲线下面积（AUC）较高，且肝硬化患者与非肝硬化患者相比，第 4 周时基线与第 4 周之间的 AUC 变化较大（3261.57 ± 1920.47ng/mL 比 1576.15 ± 911.97ng/mL，分别；P = 0.03）。报告了轻度蛋白尿（54.4%）、低磷血症（50.0%）、碳酸氢盐减少（29.4%）和低钾血症（13.2%）。血清肌酐水平未改变。
结论
LDV/SOF 在合并感染 HCV 基因型 1 和 HIV-1 的 PI 经验丰富的患者中提供了较高的 SVR 率，包括肝硬化患者。
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