Clinical Application of Direct-acting Antivirals in Hepatitis C Patients

doi:10.12114/j.issn.1007-9572.2020.00.337

Abstract

Abstract: Hepatitis C virus （HCV） infection is common in patients with chronic renal insufficiency.In those with dialysis，the risk of HCV infection is even higher.Besides，the risks of HCV-related hepatocellular carcinoma and cirrhosis are also significantly increased.In recent years，direct-acting antivirals have achieved good efficacy and safety in the treatment of chronic hepatitis C.This paper aims to summarize the application progress of DAAs in patients with hepatitis C on dialysis，conludes that G/P regimen is recommended for patients with HCV on dialysis of genotype 1-6 and SOF is not recommended for patients with hepatitis C on dialysis because of the high blood concentration of SOF in people with severe renal impairment due to renal metabolism.

Key words: Hepatitis C, Hepatitis C virus, Direct-acting antivirals, Dialysis, Review

摘要： 丙型肝炎病毒（HCV）感染在慢性肾功能不全患者中较常见，尤其是在进行透析的患者中，HCV感染较普通患者的风险极大增加，同时还会导致肝细胞癌及肝硬化的发病率明显升高。近年来直接抗病毒药物（DAAs）在慢性丙型肝炎的治疗中取得了较好的疗效及安全性，本文通过总结DAAs在丙型肝炎合并透析患者中的应用进展，发现对于基因1~6型HCV合并透析患者，推荐使用G/P方案；由于索磷布韦（SOF）经肾脏代谢，在重度肾损害人群中的血药浓度较高，因此SOF组合方案并不推荐用于丙型肝炎合并透析患者的治疗。

关键词: 丙型肝炎, 丙型肝炎病毒, 直接抗病毒药物, 透析, 综述

LIANG Wenyan,MA Aixia. Clinical Application of Direct-acting Antivirals in Hepatitis C Patients　[J]. Chinese General Practice, 2020, 23(29): 3661-3666. DOI: 10.12114/j.issn.1007-9572.2020.00.337.
梁文焰,马爱霞. 直接抗病毒药物治疗丙型肝炎合并透析患者的临床应用[J]. 中国全科医学, 2020, 23(29): 3661-3666. DOI: 10.12114/j.issn.1007-9572.2020.00.337.

References

［1］NAKAYAMA E，AKIBA T，MARUMO F，et al．Prognosis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy［J］．J Am Soc Nephrol，2000，11（10）：1896-1902.
［2］GOODKIN D A，BIEBER B，JADOUL M，et al．Mortality，hospitalization，and quality of life among patients with hepatitis C infection on hemodialysis［J］．Clin J Am Soc Nephrol，2017，12（2）：287-297．DOI：10.2215/CJN.07940716.
［3］ESPINOSA M，HERNàNDEZ J，ARENAS M D，et al．Pegylated interferon （alone or with ribavirin） for chronic hepatitis C in haemodialysis population［J］．Kidney Blood Press Res，2015，40（3）：258-265．DOI：10.1159/000368501.
［4］European Association for the Study of the Liver.EASL recommendations on treatment of hepatitis C 2016［J］．J Hepatol，2017，66（1）：153-194．DOI：10.1016/j.jhep.2016.09.001.
［5］MACDONALD A，HARRIS M.Hepatitis C virus NS5A：tales of a promiscuous protein［J］．J Gen Virol，2004，85（Pt 9）：2485-2502．DOI：10.1099/vir.0.80204-0.
［6］RUSTGI V，WEDEMEYER H，POCKROS P，et al．Sustained virologic response rate of 96% in HCV genotype 1a-infected patients treated with ombitasvir/paritaprevir/r and dasabuvir with ribavirin［J］．Am J Gastroenterol，2015，110：S862．
［7］FELD J J，MORENO C，TRINH R，et al．Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks［J］．J Hepatol，2016，64（2）：301-307．DOI：10.1016/j.jhep.2015.10.005.
［8］HéZODE C，ASSELAH T，REDDY K R，et al．Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection （PEARL-I）：a randomised，open-label trial［J］．Lancet，2015，385（9986）：2502-2509．
［9］POCKROS P J，REDDY K R，MANTRY P S，et al．Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease［J］．Gastroenterology，2016，150（7）：1590-1598．DOI：10.1053/j.gastro.2016.02.078.
［10］LAWITZ E，GANE E，COHEN E，et al．Efficacy and safety of ombitasvir/paritaprevir/ritonavir in patients with hepatitis C virus genotype 1 or 4 infection and advanced kidney disease［J］．Kidney Int Rep，2019，4（2）：257-266．DOI：10.1016/j.ekir.2018.10.003.
［11］MU?OZ-GóMEZ R，RINCóN D，AHUMADA A，et al．Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus （HCV） infection in patients with severe renal impairment：a multicentre experience［J］．J Viral Hepat，2017，24（6）：464-471．
［12］PONZIANI F R，SICILIANO M，LIONETTI R，et al．Effectiveness of paritaprevir/ritonavir/ombitasvir/dasabuvir in hemodialysis patients with hepatitis C virus infection and advanced liver fibrosis：case reports［J］．Am J Kidney Dis，2017，70（2）：297-300．DOI：10.1053/j.ajkd.2017.01.037.
［13］MCPHEE F，SHEAFFER A K，FRIBORG J，et al．Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir （BMS-650032）［J］．Antimicrob Agents Chemother，2012，56（10）：5387-5396．DOI：10.1128/AAC.01186-12.
［14］潘芝弟，林军，杨丽鸳，等．丙型肝炎病毒非结构蛋白5A抑制剂的研究进展［J］．世界临床药物，2015，36（8）：562-568．DOI：10.13683/j.wph.2015.08.013.
［15］LEE B S，SONG M J，KWON J H，et al．Efficacy and safety of daclatasvir and asunaprevir in patients with hepatitis C virus genotype 1b infection on hemodialysis［J］．Gut Liver，2019，13（2）：191-196．DOI：10.5009/gnl18240.
［16］SUDA G，KUDO M，NAGASAKA A，et al．Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C［J］．J Gastroenterol，2016，51（7）：733-740．DOI：10.1007/s00535-016-1162-8.
［17］TOYODA H，KUMADA T，TADA T，et al．Erratum to：safety and efficacy of dual direct-acting antiviral therapy （daclatasvir and asunaprevir） for chronic hepatitis C virus genotype 1 infection in patients on hemodialysis［J］．J Gastroenterol，2016，51（7）：750．DOI：10.1007/s00535-016-1192-2.
［18］KAWAKAMI Y，IMAMURA M，IKEDA H，et al．Pharmacokinetics，efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C：pilot study［J］．J Viral Hepat，2016，23（11）：850-856．DOI：10.1111/jvh.12553.
［19］SUDA G，FURUSYO N，TOYODA H，et al．Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection：a nationwide retrospective study in Japan［J］．J Gastroenterol，2018，53（1）：119-128．DOI：10.1007/s00535-017-1353-y.
［20］MIYAZAKI R，MIYAGI K.Effect and safety of daclatasvir-asunaprevir combination therapy for chronic hepatitis C virus genotype 1b -infected patients on hemodialysis［J］．Ther Apher Dial，2016，20（5）：462-467．
［21］OTSUKA T，KAWAGUCHI Y，MIZUTA T，et al．Asunaprevir and daclatasvir in hemodialysis patients with chronic hepatitis C virus genotype 1b infection［J］．JGH Open，2017，1（4）：148-152．DOI：10.1002/jgh3.12026.
［22］FDA.FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4［EB/OL］．［2019-07-20］．https：//www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2016.
［23］ROTH D，NELSON D R，BRUCHFELD A，et al．Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease （the C-SURFER study）：a combination phase 3 study［J］．Lancet，2015，386（10003）：1537-1545．DOI：10.1016/S0140-6736（15）00349-9.
［24］ALRIC L，OLLIVIER-HOURMAND I，BéRARD E，et al．Grazoprevir plus elbasvir in HCV genotype-1 or -4 infected patients with stage 4/5 severe chronic kidney disease is safe and effective［J］．Kidney Int，2018，94（1）：206-213．DOI：10.1016/j.kint.2018.02.019.
［25］FLAMM S L，BACON B，CURRY M P，et al．Real-world use of elbasvir-grazoprevir in patients with chronic hepatitis C：retrospective analyses from the TRIO network［J］．Aliment Pharmacol Ther，2018，47（11）：1511-1522．
［26］ATSUKAWA M，TSUBOTA A，TOYODA H，et al．Efficacy and safety of elbasvir/grazoprevir for Japanese patients with genotype 1b chronic hepatitis C complicated by chronic kidney disease，including those undergoing hemodialysis：a post hoc analysis of a multicenter study［J］．J Gastroenterol Hepatol，2019，34（2）：364-369．DOI：10.1111/jgh.14447.
［27］SUDA G，KUROSAKI M，ITAKURA J，et al．Safety and efficacy of elbasvir and grazoprevir in Japanese hemodialysis patients with genotype 1b hepatitis C virus infection［J］．J Gastroenterol，2019，54（1）：78-86．DOI：10.1007/s00535-018-1495-6.
［28］FDA.FDA approves Mavyret for Hepatitis C［EB/OL］．［2019-07-20］．https：//www.fda.gov/news events/press-announcements/fda-approves-mavyret-hepatitis-c.
［29］FORNS X，LEE S S，VALDES J，et al．Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1，2，4，5，or 6 infection in adults with compensated cirrhosis （EXPEDITION-1）：a single-arm，open-label，multicentre phase 3 trial［J］．Lancet Infect Dis，2017，17（10）：1062-1068．DOI：10.1016/S1473-3099（17）30496-6.
［30］GANE E，LAWITZ E，PUGATCH D，et al．Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment［J］．N Engl J Med，2017，377（15）：1448-1455．DOI：10.1056/NEJMoa1704053.
［31］KUMADA H，WATANABE T，SUZUKI F，et al．Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience，severe renal impairment，or genotype 3 infection［J］．J Gastroenterol，2018，53（4）：566-575．DOI：10.1007/s00535-017-1396-0.
［28］WEIR M R，KLINE I，XIE J，et al．Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate （eGFR）［J］．Curr Med Res Opin，2014，30（9）：1759-1768．DOI：10.1185/03007995.2014.919907.
［29］PUCKRIN R，SALTIEL M P，REYNIER P，et al．SGLT-2 inhibitors and the risk of infections：a systematic review and meta-analysis of randomized controlled trials［J］．Acta Diabetol，2018，55（5）：503-514．DOI：10.1007/s00592-018-1116-0.
［30］LIU J L，LI L，LI S Y，et al．Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus：a systematic review and meta-analysis［J］．Sci Rep，2017，7（1）：2824．DOI：10.1038/s41598-017-02733-w.
［31］HONIGBERG M C，VARDENY O，VADUGANATHAN M.Practical considerations for the use of sodium-glucose co-transporter 2 inhibitors in heart failure［J］．Circ Heart Fail，2020，13（2）：e006623．DOI：10.1161/CIRCHEARTFAILURE.119.006623.
［32］O'MEARA E，MCDONALD M，CHAN M，et al．CCS/CHFS heart failure guidelines：clinical trial update on functional mitral regurgitation，SGLT2 inhibitors，ARNI in HFpEF，and tafamidis in amyloidosis［J］．Can J Cardiol，2020，36（2）：159-169．DOI：10.1016/j.cjca.2019.11.036.
［33］BONNER C，KERR-CONTE J，GMYR V，et al．Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion［J］．Nat Med，2015，21（5）：512-517.DOI：10.1038/nm.3828.
［34］DIAZ-RAMOS A，EILBERT W，MARQUEZ D.Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use：a case report and review of the literature［J］．Int J Emerg Med，2019，12（1）：27．
［35］DANDONA P，MATHIEU C，PHILLIP M，et al．Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes：the DEPICT-1 52-week study［J］．Diabetes Care，2018，41（12）：2552-2559．DOI：10.2337/dc18-1087.
［36］TANG H L，LI D D，ZHANG J J，et al．Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes：a network and cumulative meta-analysis of randomized controlled trials［J］．Diabetes Obes Metab，2017，19（8）：1106-1115．DOI：10.1111/dom.12917.
［37］HAHN K，EJAZ A A，KANBAY M，et al．Acute kidney injury from SGLT2 inhibitors：potential mechanisms［J］．Nat Rev Nephrol，2016，12（12）：711-712．
［38］HEYMAN S N，KHAMAISI M，ROSEN S，et al．Potential hypoxic renal injury in patients with diabetes on SGLT2 inhibitors：caution regarding concomitant use of NSAIDs and iodinated contrast media［J］．Diabetes Care，2017，40（4）：e40-41.DOI：10.2337/dc16-2200.
［32］SUDA G，HASEBE C，ABE M，et al．Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection［J］．J Gastroenterol，2019，54（7）：641-649．
［33］DESNOYER A，POSPAI D，LE M P，et al．Pharmacokinetics，safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C［J］．J Hepatol，2016，65（1）：40-47．DOI：10.1016/j.jhep.2016.02.044.
［34］NAZARIO H E，NDUNGU M，MODI A A.Sofosbuvir and simeprevir in hepatitis C genotype 1-patients with end-stage renal disease on haemodialysis or GFR <30 ml/min［J］．Liver Int，2016，36（6）：798-801．DOI：10.1111/liv.13025.
［35］SAXENA V，KORAISHY F M，SISE M E，et al．Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function［J］．Liver Int，2016，36（6）：807-816．DOI：10.1111/liv.13102.
［36］SINGH T，GUIRGUIS J，ANTHONY S，et al．Sofosbuvir-based treatment is safe and effective in patients with chronic hepatitis C infection and end stage renal disease：a case series［J］．Liver Int，2016，36（6）：802-806．DOI：10.1111/liv.13078.
［37］CHOUDHARY N S，KUMAR A，BODH V，et al．Efficacy and safety of sofosbuvir-based regimens in chronic hepatitis C patients on dialysis［J］．Indian J Gastroenterol，2017，36（2）：113-116．DOI：10.1007/s12664-017-0735-7.
［38］SURENDRA M，RAJU S B，SRIDHAR N，et al．Ledipasvir and Sofosbuvir for untreated HCV genotype 1 infection in end stage renal disease patients：a prospective observational study［J］．Hemodial Int，2018，22（2）：217-221．DOI：10.1111/hdi.12604.
［39］仇丽霞，胡中杰，林伟，等．半量索非布韦联合达卡他韦治疗透析患者慢性丙型肝炎的疗效及安全性研究［J］．慢性病学杂志，2017，18（7）：727-730．DOI：10.16440/j.cnki.1674-8166.2017.07.003.
［40］HE Y L，YANG S J，HU C H，et al．Safety and efficacy of sofosbuvir-based treatment of acute hepatitis C in end-stage renal disease patients undergoing haemodialysis［J］．Aliment Pharmacol Ther，2018，47（4）：526-532．DOI：10.1111/apt.14429.
［41］GOEL A，BHADAURIA D S，KAUL A，et al．Daclatasvir and reduced-dose sofosbuvir：an effective and pangenotypic treatment for hepatitis C in patients with estimated glomerular filtration rate < 30 ml/min［J］．Nephrology （Carlton），2019，24（3）：316-321．DOI：10.1111/nep.13222.
［42］TANEJA S，DUSEJA A，DE A，et al．Low-dose sofosbuvir is safe and effective in treating chronic hepatitis C in patients with severe renal impairment or end-stage renal disease［J］．Dig Dis Sci，2018，63（5）：1334-1340．DOI：10.1007/s10620-018-4979-6.
［43］GANE E J，ROBSON R A，BONACINI M，et al．Safety，anti-viral efficacy and pharmacokinetics （PK） of sofosbuvir （SOF） in patients with severe renal impairment［EB/OL］．［2019-07-20］．http：//www.embase.com/search/results?subaction=viewrecord&from=export&id=L71639644.

[1]	DING Zijun, ZHOU Nannan, LUO Xing, LUO Jieyu, HAO Wenjuan, ZHANG Chunjiang, JIN Xin, ZHAO Dan. Cognitive Impairment in Patients on Maintenance Hemodialysis and Its Influencing Factors: a Multicenter Cross-sectional Study [J]. Chinese General Practice, 2025, 28(23): 2885-2893.
[2]	ZHU Rongfang, JIN Jingjing, LIANG Xiangnan, QIAN Yuetong, GENG Tonghui, BAI Yaling, XU Jinsheng. Correlation between Mean Platelet Volume and Vascular Access Events in Maintenance Hemodialysis Patients [J]. Chinese General Practice, 2025, 28(15): 1855-1861.
[3]	ZHU Lu, AI Jun, LIAO Shengwu, HUANG Shuting, GONG Nirong, KONG Yaozhong, LIU Dehui, DOU Xianrui, ZHANG Guangqing. Association of Prognostic Nutritional Index with Cardiovascular Mortality in Patients with Peritoneal Dialysis: a Multicenter Retrospective Cohort Study [J]. Chinese General Practice, 2025, 28(05): 568-574.
[4]	CHEN Ruman, BAI Yafei, WANG Chunli, AN Na, XU Mingzhi, HE Jiqing, QI Yonghui, WANG Liheng, LI Hong. Combined Predictive Value of Neutrophil-to-lymphocyte Ratio and C-reactive Protein-to-albumin Ratio for All-cause Mortality Risk in Patients with Maintenance Hemodialysis: Cohort Study Followed for 5 Years [J]. Chinese General Practice, 2024, 27(35): 4397-4402.
[5]	LI Yongqi, CHEN Jing, LIU Lingling, YANG Jie, GONG Yanlin, CHU Jing. Barriers and Facilitators of Implementation of Benefit Finding Promotion Program in Maintenance Hemodialysis Patients Based on the i-PARIHS Framework [J]. Chinese General Practice, 2024, 27(33): 4155-4161.
[6]	NIU Di, CHEN Ruifang, PANG Xinxin, XIAO Mingzhi, ZHANG Junshao, ZHANG Xiaowei. Correlation between Systemic Immune-inflammation Index and Erythropoietin Hypo-responsiveness in Patients with Maintenance Hemodialysis [J]. Chinese General Practice, 2024, 27(29): 3635-3640.
[7]	LI Qiuling, TANG Wenwu, YU Yiwen, DENG Huan, YANG Xiaohua, CHEN Xiaoxia, JI Yifei. Establishment and Verification of Risk Prediction Model for Silent Brain Infarction in Maintenance Hemodialysis Patients: a Multicenter Study [J]. Chinese General Practice, 2024, 27(26): 3232-3239.
[8]	ZHANG Dongliang, MA Yingchun, REN Jianwei, WANG Lei, ZHAO Jingxin, LIN Xuya. Body Composition Analysis of the Effect of Water Load Parameters on Prognosis of Patients with Different Modes of Dialysis: a Multicenter Prospective Cohort Study [J]. Chinese General Practice, 2024, 27(21): 2586-2591.
[9]	WANG Xiaoxia, CAO Xuehua, LI Yan, XIONG Langyu, HU Wanqin, XIANG Feng, JIA Yu. Prevalence and Influencing Factors of Frailty in Maintenance Hemodialysis Patients in China: a Meta-analysis [J]. Chinese General Practice, 2024, 27(20): 2534-2544.
[10]	LI Jing, MA Leilei, WANG Guanran, JIANG Chen, XING Haitao, YANG Hongtao. Analysis of Clinical Characteristics and Influencing Factors of Gastrointestinal Dysfunction Associated with Peritoneal Dialysis in Uremia [J]. Chinese General Practice, 2024, 27(18): 2198-2204.
[11]	SU Guobin, LING Xitao, DUAN Ruolan, ZHANG La, XU Yuan, PENG Yu, HOU Haijing, LIU Xusheng, LU Fuhua. Selection of Therapeutic Drugs for COVID-19 Infection in Adults with Chronic Kidney Disease Based on Medical Evidence [J]. Chinese General Practice, 2023, 26(26): 3220-3229.
[12]	YANG Changyuan, LING Xitao, HU Xiaoxuan, ZHANG La, QIN Xindong, LIU Hui, LU Fuhua, SU Guobin. Clinical Interpretation of Physical Activity and Exercise in Peritoneal Dialysis: International Society for Peritoneal Dialysis and the Global Renal Exercise Network Practice Recommendations [J]. Chinese General Practice, 2023, 26(09): 1031-1037.
[13]	HU Chunyan, LI Yajing, GENG Tonghui, ZHANG Dongxue. Protective Effect of Far Infrared Therapy Using HITH-4 Type Apparatus and External Use of Hirudoid for Autogenous Arteriovenous Fistula in Diabetic Dialysis Patients [J]. Chinese General Practice, 2023, 26(08): 951-954.
[14]	LI Jiaqing, YANG Qing, YUAN Dunlu, HUANG Jingjing, CHANG Qing, NIE Jingwen, ZHOU Zhu, LI Qing. Effectiveness and Safety of Roxadustat for Renal Anemia in Dialysis-dependent Chronic Kidney Disease: a Meta-analysis [J]. Chinese General Practice, 2023, 26(06): 704-710.
[15]	WU Xiuling, LI Jianjun, YU Ying, XING Rong, WANG Lu, WANG Xuedong, TENG Fubin. Safety of Weekly Single versus Divided Administration of Moderate-dose Erythropoietin in the Treatment of Maintenance Hemodialysis Patients with Renal Anemia [J]. Chinese General Practice, 2023, 26(06): 711-717.