Fabrizi Fabrizio, Aghemo Alessio, Lampertico Pietro, Fraquelli Mirella, Cresseri Donata, Moroni Gabriella, Passerini Patrizia, Donato Francesca M, Messa Piergiorgio
1 Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Milano, Italy.
2 Division of Gastroenterology and Hepatology, Maggiore Hospital and IRCCS Foundation, Milano, Italy.
Int J Artif Organs. 2018 Jun;41(6):306-318. doi: 10.1177/0391398818762358. Epub 2018 Mar 29.
The evidence in the medical literature on the treatment of hepatitis C virus-associated glomerular disease is extremely limited. The advent of nonconventional immunosuppressive agents and direct-acting antivirals promises high efficacy and safety.
We conducted an open-label, single-arm clinical study to examine the efficacy and safety of a combined approach for hepatitis C virus-associated glomerular disease.
In the first phase of the study, patients with hepatitis C virus-associated glomerular disease received interferon-based antiviral therapy and immunosuppressive agents; since 2013, interferon-free antiviral therapy was adopted and novel immunosuppressants (including B-cell depleting agents and mycophenolate mofetil) or immunomodulators (ribavirin) were choiced. Virological and clinical responses were evaluated over a long observation period (median follow-up of 60 weeks and 46.5 months after the end of treatment with interferon and direct-acting antiviral agents, respectively).
We enrolled 25 consecutive patients with hepatitis C virus-associated glomerular disease, 8 being liver transplant recipients for hepatitis C. A total of 13 patients received therapy with direct-acting antivirals and experienced sustained viral response (serum hepatitis C virus RNA <12 IU/mL, 12 weeks after treatment ended, sustained viral response12). The mean (±standard deviation) proteinuria decreased from 2.61 ± 1.01 at baseline to 1.71 ± 1.43 (g/day) at sustained viral response 48, p = 0.031; microscopic hematuria and serum cryoglobulins disappeared in six (50%) and seven (64%) patients, respectively, after sustained viral response by direct-acting antivirals. Adverse events occurred in 69% (9/13) of patients and were mild, with four cases of ribavirin-related anemia requiring blood transfusions (no drop-outs). After sustained viral response by direct-acting antivirals, immunosuppressive and immunomodulatory agents were initiated in clinical relapsers ( n = 2) and nonresponders ( n = 3) with some benefit. Among patients on interferon-based regimens ( n = 12), viral response (sustained viral response 24) and dropout rates were 58% (7/12) and 33% (4/12), respectively. After sustained viral response by interferon-based therapy, clinical relapsers ( n = 3) were successfully managed with immunosuppressive agents in two patients.
Treatment with direct-acting antivirals provides excellent rates of viral response and safety in patients with hepatitis C virus-related glomerular disease; viral response was frequently accompanied by clinical improvement. The absence of hepatitis C virus RNA from serum allowed immunosuppressive and immunomodulatory therapies with benefits for glomerular abnormalities and no concern on hepatitis C virus replication.
医学文献中关于丙型肝炎病毒相关性肾小球疾病治疗的证据极为有限。非传统免疫抑制剂和直接抗病毒药物的出现有望带来高效和安全的治疗效果。
我们开展了一项开放标签、单臂临床研究，以检验丙型肝炎病毒相关性肾小球疾病联合治疗方法的疗效和安全性。
在研究的第一阶段，丙型肝炎病毒相关性肾小球疾病患者接受基于干扰素的抗病毒治疗和免疫抑制剂；自2013年起，采用无干扰素抗病毒治疗，并选用新型免疫抑制剂（包括B细胞清除剂和霉酚酸酯）或免疫调节剂（利巴韦林）。在较长的观察期内评估病毒学和临床反应（分别在干扰素和直接抗病毒药物治疗结束后，中位随访时间为60周和46.5个月）。
我们连续纳入了25例丙型肝炎病毒相关性肾小球疾病患者，其中8例为丙型肝炎肝移植受者。共有13例患者接受直接抗病毒药物治疗并实现了持续病毒学应答（治疗结束12周后血清丙型肝炎病毒RNA<12 IU/mL，持续病毒学应答12）。平均（±标准差）蛋白尿从基线时的2.61±1.01降至持续病毒学应答48时的1.71±1.43（g/天），p = 0.031；在直接抗病毒药物实现持续病毒学应答后，6例（50%）患者的镜下血尿消失，7例（64%）患者的血清冷球蛋白消失。69%（9/13）的患者发生不良事件，且均为轻度，4例利巴韦林相关贫血患者需要输血（无患者退出研究）。在直接抗病毒药物实现持续病毒学应答后，对临床复发者（n = 2）和无应答者（n = 3）启动免疫抑制和免疫调节药物治疗，有一定益处。在基于干扰素方案治疗的患者（n = 12）中，病毒学应答（持续病毒学应答24）率和退出率分别为58%（7/12）和33%（4/12）。在基于干扰素的治疗实现持续病毒学应答后，2例临床复发者（n = 3）成功使用免疫抑制剂治疗。
直接抗病毒药物治疗在丙型肝炎病毒相关性肾小球疾病患者中提供了优异的病毒学应答率和安全性；病毒学应答常伴有临床改善。血清中丙型肝炎病毒RNA的消失使得免疫抑制和免疫调节治疗对肾小球异常有益，且无需担心丙型肝炎病毒复制。
