HCV resistance compartmentalization within tumoral and non-tumoral liver in transplanted patients with hepatocellular carcinoma.
Aged
Antiviral Agents
/ therapeutic use
Carcinoma, Hepatocellular
/ surgery
Coinfection
/ drug therapy
Drug Resistance, Viral
/ genetics
Drug Therapy, Combination
Genotype
Hepacivirus
/ drug effects
Hepatitis B, Chronic
/ drug therapy
Hepatitis C, Chronic
/ drug therapy
Humans
Liver Neoplasms
/ surgery
Liver Transplantation
Male
Middle Aged
Phylogeny
Ribavirin
/ therapeutic use
Sofosbuvir
/ therapeutic use
Sustained Virologic Response
Treatment Failure
Viral Nonstructural Proteins
/ genetics
Compartmentalization
HBV-coinfection
HCV
Hepatocellular carcinoma
Liver transplantation
Resistance-associated substitutions
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
08
01
2019
revised:
09
05
2019
accepted:
10
05
2019
pubmed:
7
6
2019
medline:
22
9
2020
entrez:
8
6
2019
Statut:
ppublish
Résumé
We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.
Sections du résumé
BACKGROUND & AIMS
We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis.
METHODS
Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated.
RESULTS
At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related.
CONCLUSIONS
Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.
Substances chimiques
Antiviral Agents
0
Viral Nonstructural Proteins
0
Ribavirin
49717AWG6K
Sofosbuvir
WJ6CA3ZU8B
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1986-1998Informations de copyright
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Blach S, Zeuzem S, Manns M, et al. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2(3):161-176.
Alter HJ, Houghton M. Clinical medical research award. Hepatitis C virus and eliminating post-transfusion hepatitis. Nat Med. 2000;6(10):1082-1086.
Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010;7(8):425-436. https://doi.org/10.1038/nrgastro.2010.97.
Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48(2):418-431. https://doi.org/10.1002/hep.22375.
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet. 2012;380(9859):2095-2128. https://doi.org/10.1016/S0140-6736(12)61728-0.
Pawlotsky JM, Negro F, Aghemo A, et al. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018;69(2):461-511.
Lampertico P, Agarwal K, Berg T, et al. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398.
Papadopoulos N, Papavdi M, Pavlidou A, et al. Hepatitis B and C coinfection in a real-life setting: viral interactions and treatment issues. Ann Gastroenterol. 2018;31(3):365-370. https://doi.org/10.20524/aog.2018.0255.
Mondal RK, Khatun M, Banerjee P, et al. Synergistic impact of mutations in Hepatitis B Virus genome contribute to its occult phenotype in chronic Hepatitis C Virus carriers. Sci Rep. 2017;7(1):9653. https://doi.org/10.1038/s41598-017-09965-w.
Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection. J Clin Microbiol. 1998;36(7):2084-2086.
Raimondo G, Allain J-P, Brunetto MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008;49(4):652-657. https://doi.org/10.1016/j.jhep.2008.07.014.
Blackard JT, Sherman KE. Hepatitis B virus (HBV) reactivation-The potential role of direct-acting agents for hepatitis C virus (HCV). Rev Med Virol. 2018;28(4):e1984. https://doi.org/10.1002/rmv.1984.
Barth H. Hepatitis C virus: Is it time to say goodbye yet? Perspectives and challenges for the next decade. World J Hepatol. 2015;7(5):725. https://doi.org/10.4254/wjh.v7.i5.725.
Soria A, Fabbiani M, Lapadula G, Gori A. Unexpected viral relapses in hepatitis C virus-infected patients diagnosed with hepatocellular carcinoma during treatment with direct-acting antivirals. Hepatology. 2017;66(3):992-994. https://doi.org/10.1002/hep.29181.
Prenner SB, VanWagner LB, Flamm SL, Salem R, Lewandowski RJ, Kulik L. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals. J Hepatol. 2017;66(6):1173-1181. https://doi.org/10.1016/j.jhep.2017.01.020.
Persico M, Aglitti A, Aghemo A, et al. High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma. Aliment Pharmacol Ther. 2018;47(12):1705-1712. https://doi.org/10.1111/apt.14685.
Vera-Otarola J, Barría MI, León U, et al. Hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cells of treatment naïve chronically infected patients. J Viral Hepat. 2009;16(9):633-43. https://doi.org/10.1111/j.1365-2893.2009.01112.x.
Blackard JT, Ma G, Welge JA, et al. Analysis of a non-structural gene reveals evidence of possible hepatitis C virus (HCV) compartmentalization. J Med Virol. 2012;84(2):242-252. https://doi.org/10.1002/jmv.22269.
Liou T-C, Chang T-T, Young K-C. Detection of HCV RNA in saliva, urine, seminal fluid, and ascites. J Med Virol. 1992;37(3):197-202. https://doi.org/10.1002/jmv.1890370309.
Forton DM, Taylor-Robinson S, Gess M, Thomas HC. Central nervous system complications of hepatitis C virus infection. In: Thomas HC, Lok ASF, Locarnini SA, Zuckerman AJ, eds. Viral Hepat. 4th Ed. John Wiley & Sons, Ltd; 2013: 310-324. https://doi.org/10.1002/9781118637272.ch21
Ramirez S, Perez-del-Pulgar S, Carrion JA, et al. Hepatitis C virus superinfection of liver grafts: a detailed analysis of early exclusion of non-dominant virus strains. J Gen Virol. 2010;91(5):1183-1188. https://doi.org/10.1099/vir.0.018929-0.
Morillas RM, Masnou H, Ardévol M, López D. Role of ribavirin in interferon-free therapy for the treatment of hepatitisC virus. Gastroenterol Hepatol. 2017;40(10):699-708. https://doi.org/10.1016/j.gastrohep.2017.07.003.
Mücke MM, Mücke VT, Lange CM, Zeuzem S. Managing hepatitis C in patients with the complications of cirrhosis. Liver International. 2018;38:14-20. https://doi.org/10.1111/liv.13636.
Di Maio VC, Cento V, Lenci I, et al. Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. Liver Int. 2017;37(4):514-528. https://doi.org/10.1111/liv.13327.
Cento V, Mirabelli C, Salpini R, et al. HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors. PLoS ONE. 2012;7(7):e39652. https://doi.org/10.1371/journal.pone.0039652.
Sorbo MC, Cento V, Di Maio VC, et al. Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018. Drug Resist Updates. 2018;37:17-39. https://doi.org/10.1016/j.drup.2018.01.004.
Kalaghatgi P, Sikorski AM, Knops E, et al. Geno2pheno[HCV] - A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents. PLoS One 2016; 11(5): e0155869. https://doi.org/10.1371/journal.pone.0155869
Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. 2011;28(10):2731-2739. https://doi.org/10.1093/molbev/msr121.
Stamatakis A. RAxML version 8: A tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics. 2014;30(9):1312-1313. https://doi.org/10.1093/bioinformatics/btu033.
Maimone S, Tripodi G, Musolino C, Cacciola I, Pollicino T, Raimondo G. Lack of the NS5B S282T mutation in HCV isolates from liver tissue of treatment-naive patients with HCV genotype-1b infection. Antivir Ther. 2015;20(2):245-247. https://doi.org/10.3851/IMP2844.
Maimone S, Musolino C, Squadrito G, Raffa G, Pollicino T, Raimondo G. NS3 genetic variability in HCV genotype-1b isolates from liver specimens and blood samples of treatment-naive patients with chronic hepatitis C. Antivir Ther. 2013;18(1):131-134. https://doi.org/10.3851/IMP2326.
Morsica G, Andolina A, Merli M, et al. NS3 protease resistance-associated substitutions in liver tissue and plasma samples from patients infected by hepatitis C virus genotype 1A or 1B. Arch Virol. 2017;162(8):2271-2277. https://doi.org/10.1007/s00705-017-3341-1.
Pérez PS, Di Lello FA, Mullen EG, et al. Compartmentalization of hepatitis C virus variants in patients with hepatocellular carcinoma. Mol Carcinog. 2017;56(2):371-380. https://doi.org/10.1002/mc.22500.
Harouaka D, Engle RE, Wollenberg K, et al. Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue. Proc Natl Acad Sci USA. 2016;113(5):1375-1380. https://doi.org/10.1073/pnas.1516879113.
Hedegaard DL, Tully DC, Rowe IA, et al. High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease. J Hepatol. 2017;66(1):28-38. https://doi.org/10.1016/j.jhep.2016.07.048.
Gambato M, Pérez-del-Pulgar S, Hedskog C, et al. Hepatitis C virus RNA persists in liver explants of most patients awaiting liver transplantation treated with an interferon-free regimen. Gastroenterology. 2016;151(4):633-636.e3. https://doi.org/10.1053/j.gastro.2016.06.025.
Liu M, Jiang L, Guan X-Y. The genetic and epigenetic alterations in human hepatocellular carcinoma: a recent update. Protein Cell. 2014;5(9):673-691. https://doi.org/10.1007/s13238-014-0065-9.
Diaz G, Melis M, Tice A, et al. Identification of microRNAs specifically expressed in hepatitis C virus-associated hepatocellular carcinoma. Int J Cancer. 2013;133(4):816-824. https://doi.org/10.1002/ijc.28075.
Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. World Journal of Hepatology. 2012;4(12):342. https://doi.org/10.4254/wjh.v4.i12.342.
Bertoli A, Sorbo MC, Aragri M, et al. Prevalence of single and multiple natural NS3, NS5A and NS5B resistance-associated substitutions in hepatitis C virus genotypes 1-4 in Italy. Sci Rep. 2018;8:8988.
Carlis L, Favero E, Rondinara G, et al. The role of spontaneous portosystemic shunts in the course of orthotopic liver transplantation. Transpl Int. 1992;5(1):9-14. https://doi.org/10.1007/BF00337182.
El-Shamy A, Eng FJ, Doyle EH, et al. A cell culture system for distinguishing hepatitis C viruses with and without liver cancer-related mutations in the viral core gene. J Hepatol. 2015;63(6):1323-1333. https://doi.org/10.1016/j.jhep.2015.07.024.
Di Maio VC, Cento V, Mirabelli C, et al. Hepatitis c virus genetic variability and the presence of ns5b resistance-Associated mutations as natural polymorphisms in selected genotypes could affect the response to ns5b inhibitors. Antimicrob Agents Chemother. 2014;58(5):2781-2797. https://doi.org/10.1128/AAC.02386-13.
Love RA, Brodsky O, Hickey MJ, Wells PA, Cronin CN. Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J Virol. 2009;83(9):4395-4403. https://doi.org/10.1128/JVI.02352-08.
Raimondo G, Brunetto MR, Pontisso P, et al. Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. Hepatology. 2006;43(1):100-107. https://doi.org/10.1002/hep.20944.
Wang X-X, Pan X-B, Han J-C, et al. HBsAg stimulates NKG2D receptor expression on natural killer cells and inhibits hepatitis C virus replication. Hepatobiliary Pancreat Dis Int. 2018;17(3):233-240. https://doi.org/10.1016/j.hbpd.2018.03.010.
Park CW, Cho MC, 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;2014:1-11. https://doi.org/10.1155/2014/853076.
Wedemeyer H, Cornberg M, Tegtmeyer B, Frank H, Tillmann HL, Manns MP. Isolated anti-HBV core phenotype in anti-HCV-positive patients is associated with hepatitis C virus replication. Clin Microbiol Infect. 2004;10(1):70-72. https://doi.org/10.1111/j.1469-0691.2004.00771.x.
Potthoff A, Berg T, Wedemeyer H, Group H-NBCCS. Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin. Scand J Gastroenterol. 2009;44(12):1487-1490. https://doi.org/10.3109/00365520903329585.
Chu C-J, Lee S-D. Hepatitis B virus/hepatitis C virus coinfection: epidemiology clinical features, viral interactions and treatment. J Gastroenterol Hepatol. 2008;23(4):512-520. https://doi.org/10.1111/j.1440-1746.2008.05384.x.
Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2016;15(1):132-136. https://doi.org/10.1016/j.cgh.2016.06.023.
Bahnassi AA, Zekri A-R, El-houssini S, et al. Hepatitis C virus-NS3P in relation to p53, p21waf, mdm2, p21-ras and c-erbB2 in hepatocarcinogenesis. J Gastroenterol Hepatol. 2005;20(11):1731-1740. https://doi.org/10.1111/j.1440-1746.2005.04002.x.
Chang K-C, Tseng P-L, Wu Y-Y, et al. A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. Clin Gastroenterol Hepatol. 2015;13(5):1017-1024. https://doi.org/10.1016/j.cgh.2014.10.035.
Fabris C, Falleti E, Cussigh A, et al. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: Role in the course of chronic viral hepatitis and the development of HCC. J Hepatol. 2011;54(4):716-722. https://doi.org/10.1016/j.jhep.2010.07.019.