Table Info

Table 3.

Resistance associated substitutions and genotypes/subtypes in direct-acting antivirals (DAAs) agents non-responding hepatitis C virus (HCV) infected patients

DAA	Amino acid substitutions detected in DAA failing patients	HCV genotype/subtype associated with SVR failure
SOF	159F	1a, 1b, 2a/b/c, 3a
	237G	1a, 3a, 4a/d
	282R/G/T	1a, 1b, 2a/b/c, 3a, 4a/d
	316F/H/N	1a, 1b
	320F	1a
	321A/I	1a, 1b, 3a, 4a/d
VEL	24R	1a
	28T/V	1a
	30E/K/H/V/K/L/R	1a, 3a
	31M/V/P	1a, 1b, 2a/b/c, 3a, 4a/d
	32L	1a
	58D	1a
	92K	3a
	93H/N/R/S/T/W	1a, 1b, 2a/b/c, 3a, 4a/d
VOX	36L	1a
	43S	1b
	80K/R	1a, 4a/d
	156T/V	1a,1b

SOF: sofosbuvir, NS5B-polymerase inhibitor; VEL: velpatasvir, 2nd generation of NS5A inhibitor; VOX: voxilaprevir, 2nd generation of protease inhibitor; SVR: sustained virological response

Declarations

Author contributions

HX: Writing—review & editing. JG: Writing—review & editing, Investigation, Supervision.

Conflicts of interest

Prof. Jinsheng Guo who is a Guest Editor of Exploration of Digestive Diseases, had no involvement in the decision-making or the review process of this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was funded by the National Fund of Nature Science of P.R. China [91129705, 81070340] and Shanghai Pujiang Talent Program [09PJ1402600]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2:161–76. [DOI] [PubMed]

Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–72. [DOI] [PubMed]

El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology. 2002;36:S74–83. [DOI] [PubMed]

Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59:1144–65. [DOI] [PubMed]

Carithers RL Jr. Liver transplantation. Liver Transpl. 2000;6:122–35. [DOI] [PubMed]

World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Towards ending viral hepatitis. Geneva: World Health Organization; 2016.

Purcell R. The hepatitis C virus: overview. Hepatology. 1997;26:11S–4S. [DOI] [PubMed]

Robertson B, Myers G, Howard C, Brettin T, Bukh J, Gaschen B, et al. Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses: proposals for standardization. Arch Virol. 1998;143:2493–503. [DOI] [PubMed]

Ploss A, Dubuisson J. New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets. Gut. 2012;61:i25–35. [DOI] [PubMed]

10.

Lohmann V. Hepatitis C virus RNA replication. Curr Top Microbiol Immunol. 2013;369:167–98. [DOI] [PubMed] [PMC]

11.

Rice CM. New insights into HCV replication: potential antiviral targets. Top Antivir Med. 2011;19:117–20. [PubMed] [PMC]

12.

Hedskog C, Parhy B, Chang S, Zeuzem S, Moreno C, Shafran SD, et al. Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification. Open Forum Infect Dis. 2019;6:ofz076. [DOI] [PubMed] [PMC]

13.

Family: Flaviviridae [Internet]. ICTV; c2024 [cited 2024 Jan 8]. Available from: https://ictv.global/report/chapter/flaviviridae/flaviviridae/hepacivirus

14.

Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61:77–87. [DOI] [PubMed] [PMC]

15.

Sheridan I, Pybus OG, Holmes EC, Klenerman P. High-resolution phylogenetic analysis of hepatitis C virus adaptation and its relationship to disease progression. J Virol. 2004;78:3447–54. [DOI] [PubMed] [PMC]

16.

Miura M, Maekawa S, Takano S, Komatsu N, Tatsumi A, Asakawa Y, et al. Deep-sequencing analysis of the association between the quasispecies nature of the hepatitis C virus core region and disease progression. J Virol. 2013;87:12541–51. [DOI] [PubMed] [PMC]

17.

El-Shamy A, Pendleton M, Eng FJ, Doyle EH, Bashir A, Branch AD. Impact of HCV core gene quasispecies on hepatocellular carcinoma risk among HALT-C trial patients. Sci Rep. 2016;6:27025. [DOI] [PubMed] [PMC]

18.

Park C, Cho M, Hwang K, Ko SY, Oh HB, Lee HC. Comparison of quasispecies diversity of HCV between chronic hepatitis C and hepatocellular carcinoma by Ultradeep pyrosequencing. Biomed Res Int. 2014:2014:853076. [DOI] [PubMed] [PMC]

19.

Rao H, Wei L, Lopez-Talavera JC, Shang J, Chen H, Li J, et al. Distribution and clinical correlates of viral and host genotypes in Chinese patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol. 2014;29:545–53. [DOI] [PubMed] [PMC]

20.

Nkontchou G, Ziol M, Aout M, Lhabadie M, Baazia Y, Mahmoudi A, et al. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis. J Viral Hepat. 2011;18:e516–22. [DOI] [PubMed]

21.

Mazhnaya A, Meteliuk A, Barnard T, Zelenev A, Filippovych S, Altice FL. Implementing and scaling up HCV treatment services for people who inject drugs and other high risk groups in Ukraine: An evaluation of programmatic and treatment outcomes. Int J Drug Policy. 2017;47:187–95. [DOI] [PubMed] [PMC]

22.

Flower B, Du Hong D, Vu Thi Kim H, Pham Minh K, Geskus RB, Day J, et al. Seroprevalence of Hepatitis B, C and D in Vietnam: A systematic review and meta-analysis. Lancet Reg Health West Pac. 2022;24:100468. [DOI] [PubMed] [PMC]

23.

Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med. 2013;19:859–68. [DOI] [PubMed] [PMC]

24.

Hiroishi K, Ito T, Imawari M. Immune responses in hepatitis C virus infection and mechanisms of hepatitis C virus persistence. J Gastroenterol Hepatol. 2008;23:1473–82. [DOI] [PubMed]

25.

Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs. 2021;81:419–43. [DOI] [PubMed]

26.

Umemura T, Wang RY, Schechterly C, Shih JW, Kiyosawa K, Alter HJ. Quantitative analysis of anti-hepatitis C virus antibody-secreting B cells in patients with chronic hepatitis C. Hepatology. 2006;43:91–9. [DOI] [PubMed]

27.

Sarin SK, Kumar M. Natural history of HCV infection. Hepatol Int. 2012;6:684–95. [DOI] [PubMed]

28.

Poynard T, Mathurin P, Lai CL, Guyader D, Poupon R, Tainturier M, et al.; PANFIBROSIS Group. A comparison of fibrosis progression in chronic liver diseases. J Hepatol. 2003;38:257–65. [DOI] [PubMed]

29.

Ryder SD, Irving WL, Jones DA, Neal KR, Underwood JC; Trent Hepatitis C Study Group. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study. Gut. 2004;53:451–5. [DOI] [PubMed] [PMC]

30.

Zarski JP, Mc Hutchison J, Bronowicki JP, Sturm N, Garcia-Kennedy R, Hodaj E, et al. Rate of natural disease progression in patients with chronic hepatitis C. J Hepatol. 2003;38:307–14. [DOI] [PubMed]

31.

Pradat P, Voirin N, Tillmann HL, Chevallier M, Trépo C. Progression to cirrhosis in hepatitis C patients: an age-dependent process. Liver Int. 2007;27:335–9. [DOI] [PubMed]

32.

Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepatitis C. Best Pract Res Clin Gastroenterol. 2012;26:401–12. [DOI] [PubMed]

33.

Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:529–38. [DOI] [PubMed]

34.

Palumbo E. PEG-interferon alpha-2b for acute hepatitis C: a review. Mini Rev Med Chem. 2007;7:839–43. [DOI] [PubMed]

35.

Rao A, Rule JA, Cerro-Chiang G, Stravitz RT, McGuire BM, Lee G, et al. Role of hepatitis C infection in acute liver injury/acute liver failure in North America. Dig Dis Sci. 2023;68:304–11. [DOI] [PubMed] [PMC]

36.

Bhatty SA, Shaikh NA, Akhter SS. Liver histology in hepatitis C virus positive patients with normal and elevated alanine amino transferase levels. J Pak Med Assoc. 2009;59:832–4. [PubMed]

37.

Foster GR. Quality of life considerations for patients with chronic hepatitis C. J Viral Hepat. 2009;16:605–11. [DOI] [PubMed]

38.

Younossi ZM, Stepanova M, Racila A, Afendy A, Lawitz EJ, Schwabe C, et al. Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection. Clin Gastroenterol Hepatol. 2020;18:468–76.e11. [DOI] [PubMed]

39.

Gerber L, Estep M, Stepanova M, Escheik C, Weinstein A, Younossi ZM. Effects of Viral Eradication With Ledipasvir and Sofosbuvir, With or Without Ribavirin, on Measures of Fatigue in Patients With Chronic Hepatitis C Virus Infection. Clin Gastroenterol Hepatol. 2016;14:156–64.e3. [DOI] [PubMed]

40.

Younossi ZM, Stepanova M, Henry L, Gane E, Jacobson IM, Lawitz E, et al. Effects of sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2014;12:1349–59.e13. [DOI] [PubMed]

41.

Neary MP, Cort S, Bayliss MS, Ware JE Jr. Sustained virologic response is associated with improved health-related quality of life in relapsed chronic hepatitis C patients. Semin Liver Dis. 1999;19:77–85. [PubMed]

42.

Saadoun D, Landau DA, Calabrese LH, Cacoub PP. Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford). 2007;46:1234–42. [DOI] [PubMed]

43.

Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016;63:408–17. [DOI] [PubMed] [PMC]

44.

Fabrizi F, Dixit V, Messa P. Antiviral therapy of symptomatic HCV-associated mixed cryoglobulinemia: meta-analysis of clinical studies. J Med Virol. 2013;85:1019–27. [DOI] [PubMed]

45.

Landau DA, Scerra S, Sene D, Resche-Rigon M, Saadoun D, Cacoub P. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy. J Rheumatol. 2010;37:615–21. [DOI] [PubMed]

46.

Long JD, Rutledge SM, Sise ME. Autoimmune Kidney Diseases Associated with Chronic Viral Infections. Rheum Dis Clin North Am. 2018;44:675–98. [DOI] [PubMed]

47.

Mazzaro C, Quartuccio L, Adinolfi LE, Roccatello D, Pozzato G, Nevola R, et al. A review on extrahepatic manifestations of chronic hepatitis C virus infection and the impact of direct-acting antiviral therapy. Viruses. 2021;13:2249. [DOI] [PubMed] [PMC]

48.

Wedemeyer H, Wiegand J, Cornberg M, Manns MP. Polyethylene glycol-interferon: current status in hepatitis C virus therapy. J Gastroenterol Hepatol. 2002;17:S344–50. [DOI] [PubMed]

49.

Castells L, Llaneras J, Campos-Varela I, Bilbao I, Crespo M, Len O, et al. Sofosbuvir and Daclatasvir in mono- and HIV-coinfected patients with recurrent hepatitis C after liver transplant. Ann Hepatol. 2017;16:86–93. [DOI] [PubMed]

50.

Yu ML, Chen YL, Huang CF, Lin KH, Yeh ML, Huang CI, et al. Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for treatment of recurrent chronic hepatitis C genotype 1 infection after liver transplantation: Real-world experience. J Formos Med Assoc. 2018;117:518–26. [DOI] [PubMed]

51.

Ridruejo E, Garcia-Agudo R, Mendizabal M, Aoufi-Rabih S, Dixit V, Silva M, et al. Efficacy and safety of direct-acting antiviral agents for HCV in mild-to-moderate chronic kidney disease. Nefrologia (Engl Ed). 2020;40:46–52. [DOI] [PubMed]

52.

McDonald SA, Barclay ST, Innes HA, Fraser A, Hayes PC, Bathgate A, et al. Uptake of interferon-free DAA therapy among HCV-infected decompensated cirrhosis patients and evidence for decreased mortality. J Viral Hepat. 2021;28:1246–55. [DOI] [PubMed]

53.

Programme of action to eliminate the public health hazards of hepatitis C (2021-2030) [Internet]. Health Commission of Hebei Province; cited [2024 Jan 8]. Available from: http://wsjkw.hebei.gov.cn/zcfg2/382412.jhtml

54.

Mohanty A, Salameh S, Butt AA. Impact of Direct Acting Antiviral Agent Therapy upon Extrahepatic Manifestations of Hepatitis C Virus Infection. Curr HIV/AIDS Rep. 2019;16:389–94. [DOI] [PubMed]

55.

World Health Organization. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva: World Health Organization; 2018.

56.

Huang Y, de Boer WB, Adams LA, MacQuillan G, Bulsara MK, Jeffrey GP. Clinical outcomes of chronic hepatitis C patients related to baseline liver fibrosis stage: a hospital-based linkage study. Intern Med J. 2015;45:48–54. [DOI] [PubMed]

57.

Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013;144:1450–5.e2. [DOI] [PubMed]

58.

Burgess SV, Hussaini T, Yoshida EM. Concordance of sustained virologic response at weeks 4, 12 and 24 post-treatment of hepatitis c in the era of new oral direct-acting antivirals: A concise review. Ann Hepatol. 2016;15:154–9. [DOI] [PubMed]

59.

European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol. 2020;73:1170–218. [DOI] [PubMed]

60.

Bhattacharya D, Aronsohn A, Price J, Lo Re V; AASLD-IDSA HCV Guidance Panel. Hepatitis C Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis. 2023:ciad319. [DOI] [PubMed]

61.

Su CW, Yang YY, Lin HC. Impact of etiological treatment on prognosis. Hepatol Int. 2018;12:56–67. [DOI] [PubMed]

62.

Younossi Z, Park H, Henry L, Adeyemi A, Stepanova M. Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life, and Economic Burden. Gastroenterology. 2016;150:1599–608. [DOI] [PubMed]

63.

Bertino G, Ragusa R, Corsaro LS, Frazzetto E, Messina V, Inguscio L, et al. Improvement of health-related quality of life and psychological well-being after HCV eradication with direct-acting antiviral agents. Real life setting data of an Italian cohort valued by Hepatitis Quality of Life Questionnaire (HQLQv2). Health Psychol Res. 2020;8:9450. [DOI] [PubMed] [PMC]

64.

Gao LH, Nie QH, Zhao XT. Drug-Drug Interactions of Newly Approved Direct-Acting Antiviral Agents in Patients with Hepatitis C. Int J Gen Med. 2021;14:289–301. [DOI] [PubMed] [PMC]

65.

Mangia A, Milligan S, Khalili M, Fagiuoli S, Shafran SD, Carrat F, et al. Global real-world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts. Liver Int. 2020;40:1841–52. [DOI] [PubMed] [PMC]

66.

Wedemeyer H, Di Marco V, Garcia-Retortillo M, Teti E, Fraser C, Morano Amado LE, et al. Global Real-World Evidence of Sofosbuvir/Velpatasvir as a Highly Effective Treatment and Elimination Tool in People with Hepatitis C Infection Experiencing Mental Health Disorders. Viruses. 2022;14:2493. [DOI] [PubMed] [PMC]

67.

Ren XD, Fu X, He YQ, Li CY, Guo M, Qiao M. Safety and efficacy of sofosbuvir-velpatasvir: A meta-analysis. Medicine (Baltimore). 2022;101:e31183. [DOI] [PubMed] [PMC]

68.

Gentile I, Borgia F, Buonomo AR, Zappulo E, Castaldo G, Borgia G. ABT-450: a novel protease inhibitor for the treatment of hepatitis C virus infection. Curr Med Chem. 2014;21:3261–70. [DOI] [PubMed]

69.

Chen G, Wang C, Chen J, Ji D, Wang Y, Wu V, et al. Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and meta-analysis. Hepatology. 2017;66:13–26. [DOI] [PubMed]

70.

Sarrazin C. Treatment failure with DAA therapy: Importance of resistance. J Hepatol. 2021;74:1472–82. [DOI] [PubMed]

71.

Onorato L, Pisaturo M, Starace M, Minichini C, Di Fraia A, Astorri R, et al. Virological factors associated with failure to the latest generation of direct acting agents (DAA) and re-treatment strategy: A narrative review. Viruses. 2021;13:432. [DOI] [PubMed] [PMC]

72.

Smith DA, Bradshaw D, Mbisa JL, Manso CF, Bibby DF, Singer JB, et al. Real world SOF/VEL/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy. J Viral Hepat. 2021;28:1256–64. [DOI] [PubMed]

73.

Malandris K, Kalopitas G, Theocharidou E, Germanidis G. The Role of RASs/RVs in the Current Management of HCV. Viruses. 2021;13:2096. [DOI] [PubMed] [PMC]

74.

Nguyen TK, Van Le D. Identification of NS5B resistance-associated mutations in hepatitis C virus circulating in treatment naive Vietnamese patients. Infect Drug Resist. 2022;15:1547–54. [DOI] [PubMed] [PMC]

75.

Dietz J, Müllhaupt B, Buggisch P, Graf C, Peiffer KH, Matschenz K, et al. Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure. J Hepatol. 2023;78:57–66. [DOI] [PubMed]