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直接作用抗病毒药治疗丙型肝炎病毒感染

Author
Paul J Pockros, MD
Section Editor
Adrian M Di Bisceglie, MD
Deputy Editor
Allyson Bloom, MD
Translators
卢家桀, 副主任医师，副教授

引言

人们对于丙型肝炎病毒(hepatitis C virus, HCV)基因组和蛋白质的理解已取得进步，因此能够尝试改善HCV治疗的疗效和耐受性，尤其是，据此研制了多种直接作用抗病毒药(direct-acting antiviral, DAA)，这些药物靶向作用于HCV生命周期中的特定阶段(图 1)。DAA是靶向作用于病毒的特定非结构(nonstructural, NS)蛋白的分子，可破坏病毒复制和感染。根据DAA的作用机制和治疗靶点，将其分为4类：非结构蛋白3/4A(NS3/4A)蛋白酶抑制剂(protease inhibitor, PI)、NS5B核苷多聚酶抑制剂(nucleoside polymerase inhibitor, NPI)、NS5B非核苷多聚酶抑制剂(non-nucleoside polymerase inhibitor, NNPI)，以及NS5A抑制剂[1]。

本专题将总结这些不同DAA的作用机制、药理学和使用范围。其他与慢性HCV感染治疗相关的重要问题，包括患者评估、治疗方案的选择及其他治疗问题，将在别处详细讨论。 (参见“抗病毒治疗慢性丙型肝炎病毒感染的患者评估和选择”和“成人基因1型丙型肝炎病毒慢性感染的治疗方案”和“基因2型和3型慢性丙型肝炎病毒的治疗方案”和“成人丙型肝炎病毒基因型4、5和6慢性感染的治疗方案”和“慢性丙型肝炎病毒感染的处理概述”)

许多DAA仍处于不同的研发阶段，目前尚不可用。这些将在别处详细讨论。

病毒的生命周期和复制

DAA的主要作用靶点是HCV编码的、对于该病毒复制至关重要的蛋白质(图 1)。具有传染性的病毒结构是位于脂双层中的包膜糖蛋白，后者包含病毒核心蛋白和RNA[2]。在进入细胞后，病毒RNA会通过宿主处理系统而被翻译形成一种多聚蛋白，这种蛋白会在翻译期间和之后被病毒编码的蛋白酶和宿主的蛋白酶裂解为10个成熟的病毒蛋白，包括一些NS蛋白质。参与该翻译后加工的其中一种病毒蛋白酶是NS3和NS4A蛋白的异源二聚复合体(NS3/NS4A)。NS3具有蛋白水解活性，而NS4是一种作为辅因子起作用的膜蛋白。新病毒RNA的合成发生于高度结构化的复制复合体中，这种复合体由NS3、NS4A、NS4B、NS5A和NS5B组成。NS5B是一种RNA依赖的RNA多聚酶，对于病毒复制是必需的。推测NS5A可能在复制复合体的组织以及复制的调节中发挥了作用。NS5A也参与从宿主细胞释放的病毒颗粒的装配。

DAA是NS3/4A蛋白酶、NS5A蛋白及NS5B多聚酶的抑制剂。

                   

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Literature review current through: 2017-06 . | This topic last updated: 2017-01-30.
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References
Top
  1. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012; 19:449.
  2. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19:837.
  3. Pockros PJ. New direct-acting antivirals in the development for hepatitis C virus infection. Therap Adv Gastroenterol 2010; 3:191.
  4. US Food and Drug Administration. Approval of Victrelis (boceprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV). http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm255413. (Accessed on August 1, 2013).
  5. US Food and Drug Administration. Approval of Incivek (telaprevir) a direct-acting antiviral (DAA) to treat hepatitis C virus (HCV) infection. http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=201917.
  6. Hunt D, Pockros P. What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr Gastroenterol Rep 2013; 15:303.
  7. Prescribing Information for OLYSIOTM (simeprevir): Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560. Issued November 2013.
  8. Olysio (simeprevir). US FDA approved product information. National Library of Medicine. Available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1816fd68-0ed7-4a37-84bb-e298c5ab6e28 (Accessed on November 17, 2014).
  9. FDA. Olysio U.S. prescribing information http://www.accessdata.fda.gov/drugsatfda (Accessed on October 15, 2014).
  10. Jacobson IM, Dore, GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic hCV genotype 1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial. Presented at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013. Abstract 1425.
  11. Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2, a phase III trial. Presented at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013. Abstract 1413.
  12. Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 2002; 30:883.
  13. Ali A, Aydin C, Gildemeister R, et al. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol 2013; 8:1469.
  14. Lenz O, Fevery B, Verbinnen T, et al. Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1101.
  15. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; 384:1756.
  16. Evans MJ, Rice CM, Goff SP. Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci U S A 2004; 101:13038.
  17. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog. 4, e1000032 (2008).
  18. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465:96.
  19. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879.
  20. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211.
  21. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61:1127.
  22. Sovaldi (sofosbuvir). US FDA approved product information; Foster City, CA: Gilead Sciences; December 2013.
  23. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878.
  24. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13:401.
  25. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381:2100.
  26. Fontaine H, Lazarus A, Pol S, et al. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med 2015; 373:1886.
  27. Brainard DM, McHutchison JG. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med 2015; 373:1888.
  28. FDA Hepatitis Update - Important safety information: Harvoni and Sovaldi. March 21, 2015. http://content.govdelivery.com/accounts/USFDA/bulletins/f97c71 (Accessed on March 30, 2015).
  29. Renet S, Chaumais MC, Antonini T, et al. Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. Gastroenterology 2015; 149:1378.
  30. Rajyaguru S, Xu S, Hebner C, et al. Sofosbuvir selects the NS5B S282T mutation in vitro in genotype 1-6 replicons and is not cross-resistant to resistance associated variants selected by other classes of antiviral inhibitors. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1094.
  31. Harvoni (ledipasvir-sofosbuvir). US FDA approved product information. National Library of Medicine.
  32. Svarovskaia ES, Dvory-Sobol H, Parkin N, et al. Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 2014; 59:1666.
  33. Au JS, Pockros PJ. Novel therapeutic approaches for hepatitis C. Clin Pharmacol Ther 2014; 95:78.
  34. Zepatier (elbasvir and grazoprevir). US FDA approved product information; Whitehouse Station, NJ: Merck and Co, Inc; January 2016.
  35. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern Med 2015; 163:1.
  36. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015; 385:1075.
  37. Thompson A, Zeuzem S, Rockstroh J, Kwo P, et al. The combination of elbasvir and grazoprevir ± RBV is highly effective for the treatment of GT1a-infected patients. Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015.
  38. VIEKIRA PAK (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets). US FDA approved product information. National Library of Medicine. www.dailymed.nlm.nih.gov (Accessed on January 01, 2015).
  39. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1594.
  40. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1604.
  41. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370:1983.
  42. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014; 147:359.
  43. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. October 22, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm (Accessed on October 22, 2015).