直接抗病毒药物治疗肾移植术后丙型病毒性肝炎疗效与安全性的临床观察
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摘要
目的观察直接抗病毒药物(DAAs)治疗肾移植术后丙型病毒性肝炎的疗效与安全性。方法 6例肾移植术后单纯合并丙型肝炎病毒(HCV)患者,肾移植术后时间为8~43个月(中位时间19个月),治疗前HCV病毒载量为4.03×10~3~8.18×10~7 IU/m L,免疫抑制方案为他克莫司(FK506)+吗替麦考酚酯(MMF)+泼尼松(Pred)(4例)或环孢素(Cs A)+MMF+Pred(2例),治疗前血清肌酐水平低于200μmol/L,且尿量、体质量稳定,抗病毒治疗前6个月内无重大精神刺激及创伤史。6例患者抗病毒治疗前均未行HCV病毒基因型监测,口服DAAs治疗方案为单药索非布韦(4例)、索非布韦+雷迪帕韦(1例)、索非布韦+达卡他韦(1例),疗程均为12周,治疗期间每周检测患者的全血细胞计数、血清转氨酶、肌酐、免疫抑制剂血药浓度水平,每4周检测血清HCV RNA定量。结果 6例患者中,5例患者在治疗4周时HCV RNA定量即转阴并于疗程结束后获得持续性病毒学应答(SVR),1例口服单药索非布韦的患者在疗程结束后HCV病毒载量仍高于正常值,后检查该患者病毒基因型为5型,经换用索非布韦+达卡他韦继续治疗12周后病毒载量转阴并获得SVR。6例患者治疗过程中全血细胞计数、血清转氨酶、肌酐及免疫抑制剂浓度水平均未见明显波动,不良反应为一过性皮疹(1例)及轻度眩晕(1例)。结论对于肾移植术后移植肾功能稳定的患者,服用DAAs治疗HCV安全有效,治疗药物首选索非布韦+达卡他韦联合用药。
Objective To observe the clinical efficacy and safety of direct-acting antiviral agents(DAAs) in the treatment of hepatitis C after renal transplantation. Methods Six patients were complicated with hepatitis C virus(HCV) at 8 to 43 months after renal transplantation with a median time of 19 months. Prior to treatment, the virus load was detected from 4.03×10~3 to 8.18×10~7 IU/m L. Four cases were administered with tacrolimus(FK506) + mycophenolate mofetil(MMF) + prednisone(Pred), and the remaining 2 received cyclosporin(Cs A) + MMF + Pred. The serum creatinine level was lower than 200 μmol/L. The amount of urine and body weight remained stable. No severe mental irritation or trauma history was reported within 6 months before antiviral therapy. Six patients did not receive genotype test of HCV before DAAs therapy. Four patients were administered with sofosbuvir, 1 with sofosbuvir + ledipavir and 1 with sofosbuvir + daclatasvir for 12 weeks. The complete blood cell count, serum transaminase level, creatinine level and blood concentration of immunosuppressive agents were measured each week and serum HCV RNA level was quantitatively detected every 4 weeks. Results Among 6 patients, 5 were negative for HCV at 4 weeks after DAAs therapy and obtained sustained virological response(SVR) after DAAs treatment. One case administered with sofosbuvir alone was positive for HCV after DAAs therapy. The patient wasinfected with genotype 5 HCV. After 12-week administration of sofosbuvir + daclatasvir, the patient was negative for HCV and obtained SVR. No significant changes were observed in complete blood cell count, serum transaminase level, creatinine level and blood concentration of immunosuppressive agents. Adverse reactions included evanescent eruption in 1 case and mild dizziness in 1 case. Conclusions DAAs treatment is an effective and safe approach for patients with stable renal function after renal transplantation. Combined use of sofosbuvir+ daclatasvir is recommended as the optimal therapy.
Objective To observe the clinical efficacy and safety of direct-acting antiviral agents(DAAs) in the treatment of hepatitis C after renal transplantation. Methods Six patients were complicated with hepatitis C virus(HCV) at 8 to 43 months after renal transplantation with a median time of 19 months. Prior to treatment, the virus load was detected from 4.03×10~3 to 8.18×10~7 IU/m L. Four cases were administered with tacrolimus(FK506) + mycophenolate mofetil(MMF) + prednisone(Pred), and the remaining 2 received cyclosporin(Cs A) + MMF + Pred. The serum creatinine level was lower than 200 μmol/L. The amount of urine and body weight remained stable. No severe mental irritation or trauma history was reported within 6 months before antiviral therapy. Six patients did not receive genotype test of HCV before DAAs therapy. Four patients were administered with sofosbuvir, 1 with sofosbuvir + ledipavir and 1 with sofosbuvir + daclatasvir for 12 weeks. The complete blood cell count, serum transaminase level, creatinine level and blood concentration of immunosuppressive agents were measured each week and serum HCV RNA level was quantitatively detected every 4 weeks. Results Among 6 patients, 5 were negative for HCV at 4 weeks after DAAs therapy and obtained sustained virological response(SVR) after DAAs treatment. One case administered with sofosbuvir alone was positive for HCV after DAAs therapy. The patient wasinfected with genotype 5 HCV. After 12-week administration of sofosbuvir + daclatasvir, the patient was negative for HCV and obtained SVR. No significant changes were observed in complete blood cell count, serum transaminase level, creatinine level and blood concentration of immunosuppressive agents. Adverse reactions included evanescent eruption in 1 case and mild dizziness in 1 case. Conclusions DAAs treatment is an effective and safe approach for patients with stable renal function after renal transplantation. Combined use of sofosbuvir+ daclatasvir is recommended as the optimal therapy.
引文
[1]Fabrizi F,Martin P,Dixit V,et al.Meta-analysis of observational studies:hepatitis C and survival after renal transplant[J].J Viral Hepat,2014,21(5):314-324.DOI:10.1111/jvh.12148.
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[4]中华医学会肝病学分会,中华医学会感染病学分会.丙型肝炎防治指南(2015更新版)[J].中华肝脏病杂志,2015,23(12):906-923.DOI:10.3760/cma.j.issn.1007-3418.2015.12.003.Branch of Hepatology of Chinese Medical Association,Branch of Infectious Diseases of Chinese Medical Association.The guideline of prevention and treatment for hepatitis C:a 2015 update[J].Chin J Hepatol,2015,23(12):906-923.DOI:10.3760/cma.j.issn.1007-3418.2015.12.003.
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[6]Morales JM,Fabrizi F.Hepatitis C and its impact on renal transplantation[J].Nat Rev Nephrol,2015,11(3):172-182.DOI:10.1038/nrneph.2015.5.
[7]Kidney Disease:Improving Global Outcomes(KDIGO).KDIGO clinical practice guidelines for the prevention,diagnosis,evaluation,and treatment of hepatitis C in chronic kidney disease[J].Kidney Int Suppl,2008(109):S1-S99.DOI:10.1038/ki.2008.81.
[8]Chevaliez S.Antiviral activity of the new DAAs for the treatment of hepatitis C virus infection:virology and resistance[J].Clin Res Hepatol Gastroenterol,2011,35(Suppl 2):S46-S51.DOI:10.1016/S2210-7401(11)70007-9.
[9]Cortez KJ,Kottilil S.Beyond interferon:rationale and prospects for newer treatment paradigms for chronic hepatitis C[J].Ther Adv Chronic Dis,2015,6(1):4-14.DOI:10.1177/2040622314551934.
[10]Aghemo A,De Francesco R.New horizons in hepatitis C antiviral therapy with direct-acting antivirals[J].Hepatology,2013,58(1):428-438.DOI:10.1002/hep.26371.
[11]Kohler JJ,Nettles JH,Amblard F,et al.Approaches to hepatitis C treatment and cure using NS5A inhibitors[J].Infect Drug Resist,2014,7:41-56.DOI:10.2147/IDR.S36247.
[12]Nitta S,Asahina Y,Matsuda M,et al.Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents[J].Sci Rep,2016,6:34652.DOI:10.1038/srep34652.
[13]Carpio R,Pamugas GE,Danguilan R,et al.Outcomes of renal allograft recipients with hepatitis C[J].Transplant Proc,2016,48(3):836-839.DOI:10.1016/j.transproceed.2016.02.050.
[14]Bonacci M,Londo?o MC,Esforzado N,et al.Antiviral treatment with sofosbuvir and simeprevir in a kidney transplant recipient with HCV-decompensated cirrhosis:viral eradication and removal from the liver transplant waiting list[J].Transpl Int,2015,28(11):1345-1349.DOI:10.1111/tri.12622.
[15]Papayannis I,Patel P.Successful treatment of a hepatitis C-positive patient who received kidney transplant from a hepatitis C-positive donor:a case report[J].Prog Transplant,2016,26(3):238-240.DOI:10.1177/1526924816654374.
[16]Sawinski D,Kaur N,Ajeti A,et al.Successful treatment of hepatitis C in renal transplant recipients with directacting antiviral agents[J].Am J Transplant,2016,16(5):1588-1595.DOI:10.1111/ajt.13620.
[17]张霞霞,徐小元.丙型肝炎直接抗病毒药物治疗的临床应用及管理——2015年美国肝病学会丙型肝炎指南解读[J].临床肝胆病杂志,2015,31(11):1801-1802.DOI:10.3969/j.issn.1001-5256.2015.11.008.Zhang XX,Xu XY.Clinical application and management of DAA therapy for hepatitis C:an interpretation of2015 AASLD guidelines for the management of hepatitis C[J].J Clin Hepatol,2015,31(11):1801-1802.DOI:10.3969/j.issn.1001-5256.2015.11.008.
[18]童汪霞,朱建芸,雷姿颖,等.HCV在中国流行多样性和独特生长史的分析[J].中华实验和临床病毒学杂志,2014,28(5):336-338.DOI:10.3760/cma.j.issn.1003-9279.2014.05.006.Tong WX,Zhu JY,Lei ZY,et al.Great variety and unique growth history of HCV in China[J].Chin J Exp Clin Virol,2014,28(5):336-338.DOI:10.3760/cma.j.issn.1003-9279.2014.05.006.
[2]Wei F,Liu J,Liu F,et al.Interferon-based antiviral therapy for hepatitis C virus infection after renal transplantation:an updated meta-analysis[J].PLo S One,2014,9(4):e90611.DOI:10.1371/journal.pone.0090611.
[3]Gaglio PJ,Moss N,Mc Gaw C,et al.Direct-acting antiviral therapy for hepatitis C:attitudes regarding future use[J].Dig Dis Sci,2011,56(5):1509-1515.DOI:10.1007/s10620-011-1604-3.
[4]中华医学会肝病学分会,中华医学会感染病学分会.丙型肝炎防治指南(2015更新版)[J].中华肝脏病杂志,2015,23(12):906-923.DOI:10.3760/cma.j.issn.1007-3418.2015.12.003.Branch of Hepatology of Chinese Medical Association,Branch of Infectious Diseases of Chinese Medical Association.The guideline of prevention and treatment for hepatitis C:a 2015 update[J].Chin J Hepatol,2015,23(12):906-923.DOI:10.3760/cma.j.issn.1007-3418.2015.12.003.
[5]Boratyńska M,Wakulenko A,Klinger M,et al.Chronic allograft dysfunction in kidney transplant recipients:long-term single-center study[J].Transplant Proc,2014,46(8):2673-2677.DOI:10.1016/j.transproceed.2014.09.058.
[6]Morales JM,Fabrizi F.Hepatitis C and its impact on renal transplantation[J].Nat Rev Nephrol,2015,11(3):172-182.DOI:10.1038/nrneph.2015.5.
[7]Kidney Disease:Improving Global Outcomes(KDIGO).KDIGO clinical practice guidelines for the prevention,diagnosis,evaluation,and treatment of hepatitis C in chronic kidney disease[J].Kidney Int Suppl,2008(109):S1-S99.DOI:10.1038/ki.2008.81.
[8]Chevaliez S.Antiviral activity of the new DAAs for the treatment of hepatitis C virus infection:virology and resistance[J].Clin Res Hepatol Gastroenterol,2011,35(Suppl 2):S46-S51.DOI:10.1016/S2210-7401(11)70007-9.
[9]Cortez KJ,Kottilil S.Beyond interferon:rationale and prospects for newer treatment paradigms for chronic hepatitis C[J].Ther Adv Chronic Dis,2015,6(1):4-14.DOI:10.1177/2040622314551934.
[10]Aghemo A,De Francesco R.New horizons in hepatitis C antiviral therapy with direct-acting antivirals[J].Hepatology,2013,58(1):428-438.DOI:10.1002/hep.26371.
[11]Kohler JJ,Nettles JH,Amblard F,et al.Approaches to hepatitis C treatment and cure using NS5A inhibitors[J].Infect Drug Resist,2014,7:41-56.DOI:10.2147/IDR.S36247.
[12]Nitta S,Asahina Y,Matsuda M,et al.Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents[J].Sci Rep,2016,6:34652.DOI:10.1038/srep34652.
[13]Carpio R,Pamugas GE,Danguilan R,et al.Outcomes of renal allograft recipients with hepatitis C[J].Transplant Proc,2016,48(3):836-839.DOI:10.1016/j.transproceed.2016.02.050.
[14]Bonacci M,Londo?o MC,Esforzado N,et al.Antiviral treatment with sofosbuvir and simeprevir in a kidney transplant recipient with HCV-decompensated cirrhosis:viral eradication and removal from the liver transplant waiting list[J].Transpl Int,2015,28(11):1345-1349.DOI:10.1111/tri.12622.
[15]Papayannis I,Patel P.Successful treatment of a hepatitis C-positive patient who received kidney transplant from a hepatitis C-positive donor:a case report[J].Prog Transplant,2016,26(3):238-240.DOI:10.1177/1526924816654374.
[16]Sawinski D,Kaur N,Ajeti A,et al.Successful treatment of hepatitis C in renal transplant recipients with directacting antiviral agents[J].Am J Transplant,2016,16(5):1588-1595.DOI:10.1111/ajt.13620.
[17]张霞霞,徐小元.丙型肝炎直接抗病毒药物治疗的临床应用及管理——2015年美国肝病学会丙型肝炎指南解读[J].临床肝胆病杂志,2015,31(11):1801-1802.DOI:10.3969/j.issn.1001-5256.2015.11.008.Zhang XX,Xu XY.Clinical application and management of DAA therapy for hepatitis C:an interpretation of2015 AASLD guidelines for the management of hepatitis C[J].J Clin Hepatol,2015,31(11):1801-1802.DOI:10.3969/j.issn.1001-5256.2015.11.008.
[18]童汪霞,朱建芸,雷姿颖,等.HCV在中国流行多样性和独特生长史的分析[J].中华实验和临床病毒学杂志,2014,28(5):336-338.DOI:10.3760/cma.j.issn.1003-9279.2014.05.006.Tong WX,Zhu JY,Lei ZY,et al.Great variety and unique growth history of HCV in China[J].Chin J Exp Clin Virol,2014,28(5):336-338.DOI:10.3760/cma.j.issn.1003-9279.2014.05.006.