Thévenot Thierry, Elkrief Laure, Bureau Christophe, Bardou-Jacquet Edouard, Rosa Isabelle, Nguyen-Khac Eric, Oberti Frédéric, Pitta Anais, Mallet Maxime, Lebossé Fanny, Louvet Alexandre, Meunier Lucy, Nahon Pierre, Ollivier-Hourmand Isabelle, Anty Rodolphe, Francoz Claire, Riachi Ghassan, Meunier Alexandre, Cervoni Jean-Paul, Tio Gregory, Muller Allison, Curé-Martin Audace, Ladeira Ruben, Clairet Anne-Laure, Hocquet Didier, Di Martino Vincent, Weil Delphine, Desmarets Maxime
CHU Besançon, Service d'Hépatologie, Besançon, France; Université Marie et Louis Pasteur, EFS, INSERM, UMR 1098 RIGHT, F-25000 Besançon, France.
Service d'Hépato-Gastroentérologie, Hôpital Trousseau, Avenue de la République, 37170 Chambray-lès-tours, France.
J Hepatol. 2025 Jul 11. doi: 10.1016/j.jhep.2025.06.019.
BACKGROUND & AIMS: Evidence supporting primary prophylaxis of spontaneous bacterial peritonitis (SBP) is weak and the selection of quinolone-resistant bacteria is a concern. Herein, we present results from a randomized, double-blind, placebo (PBO)-controlled trial to assess whether rifaximin (RFX) has a beneficial effect on 12-month survival in patients with severe cirrhosis and ascites.
In this trial conducted at 17 French centers, patients with severe cirrhosis and grade 2 or 3 ascites and ascites protein level <15 g/L were randomized 1:1 to receive RFX 550 mg or PBO twice daily for 12 months, as primary prophylaxis for SBP. The primary endpoint was 12-month survival. Secondary endpoints were 3- and 6-month survival, incidence of complications of cirrhosis, and safety of RFX.
Between 2018 and 2022, 1,957 patients with cirrhosis and ascites were screened, 159 were randomized, and 152 (80/72 PBO/RFX) were analyzed in the modified intention-to-treat population. RFX did not improve 12-month (PBO vs. RFX: 68.1%, 95% CI 56.2-78.7 vs. 56.6%, 95% CI 43.5-67.8; p = 0.74), 6-month (71.1%, 95% CI 59.5-80.0 vs. 76.4%, 95% CI 64.3-84.8) or 3-month (75.4%, 95% CI 64.1-83.5 vs. 82.6%, 95% CI 71.4-89.7) survival, or the incidence of liver complications (SBP, encephalopathy, gastrointestinal bleeding or hepatorenal syndrome). In the per-protocol population (127 patients adherent to the study drug), a lower 12-month cumulative incidence of liver-related events was observed in the RFX group. RFX was well tolerated throughout the study.
RFX had no beneficial effect in terms of 12-month survival or incidence of complications of cirrhosis in patients with severe cirrhosis and low ascitic fluid protein levels. However, improved adherence may help reduce liver-related complications.
Selective gut decontamination using norfloxacin is the standard of care for secondary prophylaxis of spontaneous bacterial peritonitis (SBP). Evidence for primary prophylaxis of SBP is weaker, and fluoroquinolones have been associated with an increased risk of antimicrobial resistance. Rifaximin, a well-tolerated broad-spectrum antibiotic associated with a lower risk of antimicrobial resistance emergence, may be an alternative to norfloxacin. Our trial did not demonstrate an improvement in survival or liver complications (SBP, gastrointestinal bleeding, hepatic encephalopathy or hepatorenal syndrome) at 12 months with rifaximin as primary prophylaxis for SBP vs. placebo. However, in the subgroup of patients who adhered to rifaximin, liver complications decreased. Our study underlines the importance of treatment adherence in clinical trials to ensure accurate assessment of outcomes.
NCT03069131.
支持自发性细菌性腹膜炎（SBP）一级预防的证据不足，且喹诺酮耐药菌的选择是一个令人担忧的问题。在此，我们展示了一项随机、双盲、安慰剂（PBO）对照试验的结果，以评估利福昔明（RFX）对严重肝硬化和腹水患者12个月生存率是否有有益影响。
在法国17个中心进行的这项试验中，将严重肝硬化且腹水为2级或3级、腹水蛋白水平<15 g/L的患者按1:1随机分组，接受每日两次550 mg RFX或PBO治疗12个月，作为SBP的一级预防。主要终点是12个月生存率。次要终点是3个月和6个月生存率、肝硬化并发症的发生率以及RFX的安全性。
2018年至2022年期间，对1957例肝硬化和腹水患者进行了筛查，159例患者被随机分组，在改良意向性治疗人群中分析了152例（PBO组72例，RFX组80例）。RFX并未改善12个月（PBO组与RFX组：68.1%，95%CI 56.2 - 78.7 vs. 56.6%，95%CI 43.5 - 67.8；p = 0.74）、6个月（71.1%，95%CI 59.5 - 80.0 vs. 76.4%，95%CI 64.3 - 84.8）或3个月（75.4%，95%CI 64.1 - 83.5 vs. 82.6%，95%CI 71.4 - 89.7）生存率，也未改善肝硬化并发症（SBP、肝性脑病、胃肠道出血或肝肾综合征）的发生率。在符合方案人群（127例坚持使用研究药物的患者）中，RFX组观察到较低的12个月肝脏相关事件累积发生率。在整个研究过程中，RFX耐受性良好。
对于严重肝硬化且腹水蛋白水平低的患者，RFX在12个月生存率或肝硬化并发症发生率方面没有有益影响。然而，提高依从性可能有助于减少肝脏相关并发症。
使用诺氟沙星进行选择性肠道去污是自发性细菌性腹膜炎（SBP）二级预防的标准治疗方法。SBP一级预防的证据较弱，且氟喹诺酮类药物与抗菌药物耐药风险增加有关。利福昔明是一种耐受性良好的广谱抗生素，抗菌药物耐药出现风险较低，可能是诺氟沙星的替代药物。我们的试验未证明以RFX作为SBP一级预防与安慰剂相比，在12个月时生存率或肝脏并发症（SBP、胃肠道出血、肝性脑病或肝肾综合征）有改善。然而，在坚持使用RFX的患者亚组中，肝脏并发症有所减少。我们的研究强调了临床试验中治疗依从性对于确保准确评估结果的重要性。
NCT03069131。
