Occult Hepatitis C Infection in Kidney Transplant and Hemodialysis Patients Identified five to Eight Years after Sustained Virological Response

Eliane Silva*; Sara Marques; Tereza Almeida1; Fabiana Neves; Maria Dias Lopes; Josu00e9 Filipe Santos; Jorge Leitu00e3o; Adu00e9lia Simu00e3o; Armando Carvalho

**Eliane Silva*, Sara Marques, Tereza Almeida1, Fabiana Neves, Maria Dias Lopes, Josu00e9 Filipe Santos, Jorge Leitu00e3o, Adu00e9lia Simu00e3o and Armando Carvalho**

Volume5-Issue9
Dates: Received: 2024-09-08 | Accepted: 2024-09-20 | Published: 2024-09-20
Pages: 1152-1163

Abstract

Background: Occult Hepatitis C Infection (OCI) is characterized by the detection of Hepatitis C Virus (HCV) RNA in hepatocytes and in Peripheral Blood Mononuclear Cells (PBMCs) with no detection in serum, and PBMCs and Red Blood Cells (RBCs) were more recently suggested as predictors for OCI characterization. Here we aimed to evaluate OCI in Kidney Transplanted Patients (KTRs) and in Hemodialysis Patients (HD) treated with Direct-Acting Antivirals (DAAs) five to nine years after achieved a Sustained Virological Response (SVR).

Methods: Nineteen patients-SVR12 were included in this study, 12 in the KTRs and 7 in the HD study groups. HCV/OCI-RNA was screened in serum, plasma, PBMCs and RBCs five to nine years after SVR by droplet digital PCR (ddPCR) for OCI identification. Next-Generation Sequencing (NGS) was performed to characterize the viruses detected by ddPCR.

Results: In total, OCI (10.5%) and OCI RBCs (15.8%) patients were identified by ddPCR, 8.3% (both) of OCI (patient 7) and OCI RBCs (patient 9) in the KTRs, and 14.3% and 28.6% of OCI (patient 17) and OCI RBCs (patient 13 e 16) in the HD patients, respectively. HCV/OCI-RNA higher detection was in RBCs-HD (28.6%, n = 7) and PBMCs-KTRs (16.7%, n = 12) by ddPCR. HCV/OCI-RNA was not detected in analyzed samples by NGS.

Conclusion: OCI and OCI RBCs patients were identified in the KTRs and HD study groups by ddPCR suggesting that these patients might experience a relapse. PBMCs and RBCs could be predictors for HCV/OCI prevention, diagnosis and management in the study groups. These and a larger number of patients in both study groups should be evaluated in the future for a better understanding of these findings, as well as, their associated epidemiological and clinical significance.

FullText HTML FullText PDF DOI: 10.37871/jbres2003

Certificate of Publication

Copyright

How to cite this article

Silva E, Marques S, Almeida T, Neves F, Lopes MD, Santos JF, Leitão J, Simão A, Carvalho A. Occult Hepatitis C Infection in Kidney Transplant and Hemodialysis Patients Identifi ed fi ve to Eight Years after Sustained Virological Response. J Biomed Res Environ Sci. 2024 Sept 20; 5(9): 1152-1163. doi: 10.37871/jbres2003, Article ID: JBRES2003, Available at: https://www.jelsciences. com/articles/jbres2003.pdf

Subject area(s)

Biology

Infectious Diseases

Virology

References

Dolatimehr F, Khosravi MH, Rezaee-Zavareh MS, Alavian SM. Prevalence of occult HCV infection in emodialysis and kidney-transplanted patients: A systematic review. Future Virology. 2017;12(5):315-22. doi: 10.2217/fvl-2016-0138.
Rostami Z, Nourbala MH, Alavian SM, Bieraghdar F, Jahani Y, Einollahi B. The impact of Hepatitis C virus infection on kidney transplantation outcomes: A systematic review of 18 observational studies: The impact of HCV on renal transplantation. Hepat Mon. 2011;11(4):247-54. PMID: 22087151.
Alavian SM, Kabir A, Ahmadi AB, Lankarani KB, Shahbabaie MA, Ahmadzad-Asl M. Hepatitis C infection in hemodialysis patients in Iran: a systematic review. Hemodial Int. 2010;14(3):253-62. doi: 10.1111/j.1542-4758.2010.00437.x. PMID: 20491973.
Castillo I, Pardo M, Bartolomé J, Ortiz-Movilla N, Rodríguez-Iñigo E, de Lucas S, Salas C, Jiménez-Heffernan JA, Pérez-Mota A, Graus J, López-Alcorocho JM, Carreño V. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown. J Infect Dis. 2004;189(1):7-14. doi: 10.1086/380202. PMID: 14702147.
Silva E, Marques S,Osorio H, Canhão B, Madaleno J, Simão A, Carvalho A. Occult hepatitis C infection: Viruses with infectious potential in Huh7.5 and MDBK cell lines suggest HCV/OCI transmission. Pharmacy & Pharmacology International Journal. 2023. doi: 10.15406/ppij.2023.11.00394.
El-Shishtawy S, Sherif N, Abdallh E, Kamel L, Shemis M, Saleem AA, Abdalla H, El Din HG. Occult Hepatitis C Virus Infection in Hemodialysis Patients; Single Center Study. Electron Physician. 2015;7(8):1619-25. doi: 10.19082/1619. PMID: 26816589.
Baid-Agrawal S, Schindler R, Reinke P, Staedtler A, Rimpler S, Malik B, Frei U, Berg T. Prevalence of occult hepatitis C infection in chronic hemodialysis and kidney transplant patients. Journal of Hepatology. 2014;60(5):928-33. doi: 10.1016/j.jhep.2014.01.012.
Bayani M, Hasanjani Roushan MR, Soleimani Amiri MJ, Yahyapour Y, Ebrahimpour S, Akbarzadeh Jelodar S. Prevalence of occult hepatitis C virus infection in hemodialysis patients. Caspian J Intern Med. 2021;12(4):533-8. doi: 10.22088/cjim.12.4.533. PMID: 34820059.
Naghdi R, Ranjbar M, Bokharaei-Salim F, Keyvani H, Savaj S, Ossareh S, Shirali A, Mohammad-Alizadeh AH. Occult Hepatitis C Infection Among Hemodialysis Patients: A Prevalence Study. Ann Hepatol. 2017;16(4):510-3. doi: 10.5604/01.3001.0010.0277. PMID: 28611267.
Abdelmoemen G, Khodeir SA, Abou-Saif S, Kobtan A, Abd-Elsalam S. Prevalence of occult hepatitis C virus among hemodialysis patients in Tanta university hospitals: a single-center study. Environ Sci Pollut Res Int. 2018;25(6):5459-64. doi: 10.1007/s11356-017-0897-y. PMID: 29214477.
Nakhaie M, Taheri E, Charostad J, Arefinia N, Kalantar-Neyestanaki D, Rezaei Zadeh Rukerd M, Ahmadpour F, Pourebrahimi MH, Ahmadinejad Farsangi S, Shafieipour S. Prevalence of hepatitis C virus and its occult infection in hemodialysis patients. Jundishapur J Microbiol. 2023;16(5):e136504. doi: 10.5812/jjm-136504.
Naguib H, Abouelnaga SF, Elsayed MM. Occult hepatitis C virus infection in hemodialysis patients who achieved a sustained virological response to directly acting antiviral drugs: is it a concern? Int Urol Nephrol. 2024;56(1):217-22. doi: 10.1007/s11255-023-03621-1. PMID: 37209238.
Austria A, Wu GY. Occult Hepatitis C Virus Infection: A Review. J Clin Transl Hepatol. 2018;6(2):155-60. doi: 10.14218/jcth.2017.00053. PMID: 29951360.
Wróblewska A, Bielawski KP, Sikorska K. Occult Infection with hepatitis C virus: Looking for clear-cut boundaries and methodological consensus. Journal of Clinical Medicine. 2021;10(24):5874. doi: 10.3390/jcm10245874.
Taherpour S, Javanmard D, Ziaee M. Occult Hepatitis C Virus Infection among Hemodialysis Patients: An Iranian Experience. Arch Iran Med. 2020;23(9):586-92. Epub 20200901. doi: 10.34172/aim.2020.68. PMID: 32979904.
Ali NK, Mohamed RR, Saleh BE, Alkady MM, Farag ES. Occult hepatitis C virus infection among haemodialysis patients. Arab J Gastroenterol. 2018;19(3):101-5. Epub 20180920. doi: 10.1016/j.ajg.2018.09.001. PMID: 30245116.
Jiménez C, Olea T, Santana M, Lopez M, Castillo I, Bartolomé J, Quiroga J, Vaca M, Carreño V, Selgas R. Occult Hepatitis C Virus in Recipients of Kidney Transplantation: Prevalence and Clinical Implications. Transplantation. 2018;102:S658. doi: 10.1097/01.tp.0000543589.88342.67. PMID: 00007890-201807001-01058.
Iliescu EL, Mercan-Stanciu A, Toma L. Safety and efficacy of direct-acting antivirals for chronic hepatitis C in patients with chronic kidney disease. BMC Nephrology. 2020;21(1):21. doi: 10.1186/s12882-020-1687-1.
Agarwal SK, Bagchi S, Yadav RK. Hemodialysis Patients Treated for Hepatitis C Using a Sofosbuvir-based Regimen. Kidney Int Rep. 2017;2(5):831-5. doi: 10.1016/j.ekir.2017.04.003. PMID: 29270489.
Fabrizi F, Cerutti R, Messa P. An updated view on the antiviral therapy of hepatitis C in chronic kidney disease. Pathogens. 2021;10(11):1381. doi: 10.3390/pathogens10111381.
Ryu JE, Song MJ, Kim SH, Kwon JH, Yoo SH, Nam SW, Nam HC, Kim HY, Kim CW, Yang H, Bae SH, Song DS, Chang UI, Yang JM, Lee SW, Lee HL, Lee SK, Sung PS, Jang JW, Choi JY, Yoon SK. Safety and effectiveness of direct-acting antivirals in patients with chronic hepatitis C and chronic kidney disease. Korean J Intern Med. 2022;37(5):958-68. doi: 10.3904/kjim.2021.486. PMID: 35981893.
Yousif MM, Elsadek Fakhr A, Morad EA, Kelani H, Hamed EF, Elsadek HM, Zahran MH, Fahmy Afify A, Ismail WA, Elagrody AI, Ibrahim NF, Amer FA, Zaki AM, Sadek A, Shendi AM, Emad G, Farrag HA. Prevalence of occult hepatitis C virus infection in patients who achieved sustained virologic response to direct-acting antiviral agents. Infez Med. 2018;26(3):237-43. PMID: 30246766.
Mekky MA, Sayed HI, Abdelmalek MO, Saleh MA, Osman OA, Osman HA, Morsy KH, Hetta HF. Prevalence and predictors of occult hepatitis C virus infection among Egyptian patients who achieved sustained virologic response to sofosbuvir/daclatasvir therapy: a multi-center study. Infect Drug Resist. 2019;12:273-9. doi: 10.2147/idr.S181638. PMID: 30774394.
Kamar N, Marion O, Rostaing L, Cointault O, Ribes D, Lavayssière L, Esposito L, Del Bello A, Métivier S, Barange K, Izopet J, Alric L. Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation. Am J Transplant. 2016;16(5):1474-9. doi: 10.1111/ajt.13518. PMID: 26587971.
Colombo M, Aghemo A, Liu H, Zhang J, Dvory-Sobol H, Hyland R, Yun C, Massetto B, Brainard DM, McHutchison JG, Bourlière M, Peck-Radosavljevic M, Manns M, Pol S. Treatment With Ledipasvir-Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial. Ann Intern Med. 2017;166(2):109-17. doi: 10.7326/m16-1205. PMID: 27842383.
Morales AL, Liriano-Ward L, Tierney A, Sang M, Lalos A, Hassan M, Nair V, Schiano T, Satoskar R, Smith C. Ledipasvir/sofosbuvir is effective and well tolerated in postkidney transplant patients with chronic hepatitis C virus. Clin Transplant. 2017;31(5). doi: 10.1111/ctr.12941. PMID: 28239909.
Reau N, Kwo PY, Rhee S, Brown RS, Agarwal K, Angus P, Gane E, Kao JH, Mantry PS, Reddy KR, Tran TT, Hu YB, Gulati A, Ng TI, Dumas EO, Shulman N, Trinh R, Forns X. LBO-03 - MAGELLAN-2: Safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection. Journal of Hepatology. 2017;66(1, Supplement):S90-S1. doi: 10.1016/S0168-8278(17)30444-0.
Chute DF, Chung RT, Sise ME. Direct-acting antiviral therapy for hepatitis C virus infection in the kidney transplant recipient. Kidney International. 2018;93(3):560-7. doi: 10.1016/j.kint.2017.10.024.
Weigert A, Querido S, Carvalho L, Lebre L, Chagas C, Matias P, Birne R, Nascimento C, Jorge C, Adragão T, Bruges M, Machado D. Hepatitis C Virus Eradication in Kidney Transplant Recipients: A Single-Center Experience in Portugal. Transplant Proc. 2018;50(3):743-5. doi: 10.1016/j.transproceed.2018.02.017. PMID: 29661427.
Calça R, Jorge C, Lebre L, Cacheira E, Querido S, Nascimento C, Adragão T, Bruges M, Weigert A, Machado D. Hepatocellular carcinoma after direct-acting antiviral therapy in kidney transplant recipients infected with hepatitis C virus. Nefrología (English Edition). 2020;40(6):675-6. doi: 10.1016/j.nefroe.2020.11.006.
Gelpi R, Rodríguez-Villar C, Paredes D, Roque R, Ruiz A, Adalia R, de Sousa E, Revuelta I, Sole M, Martinez M, Navarro M, Lens S, Oppenheimer F, Diekmann F. Safety of hepatitis C virus (HCV)-treated donors for kidney transplantation excluding occult HCV infection through kidney biopsies. Transplant International. 2018;31(8):938-9. doi: 10.1111/tri.13270.
Czarnecka P, Czarnecka K, Tronina O, Bączkowska T, Wyczałkowska-Tomasik A, Durlik M, Czerwinska K. Evaluation of long-term outcomes of direct acting antiviral agents in chronic kidney disease subjects: A single center cohort study. J Clin Med. 2023;12(10):3513. doi: 10.3390/jcm12103513.
Silva E, Marques S, Salta S, Serqueira JP, Madaleno J, Simão A, Carvalho A. Occult hepatitis C infection detection in people who use drugs with or without direct-antiviral agents therapy. J Hepatol. 2022.
Silva E, Marques S, Leal B, Canhao B, Madaleno J, Simao A, Carvalho A. Occult hepatitis C infection identified in injection drug users with direct antiviral agents therapy and spontaneous resolution of hepatitis C virus infection. Virus Res. 2023;329:199104. doi: 10.1016/j.virusres.2023.199104. PMID: 37003528.
Costa-Matos L, Batista P, Monteiro N, Henriques P, Girao F, Carvalho A. Hfe mutations and iron overload in patients with alcoholic liver disease. Arq Gastroenterol. 2013;50(1):35-41. doi: 10.1590/s0004-28032013000100008. PMID: 23657305.
Silva E, Marques S, Osório H, Carvalheira J, Thompson G. Endogenous hepatitis C virus homolog fragments in European rabbit and hare genomes replicate in cell culture. PLoS One. 2012;7(11):e49820. doi: 10.1371/journal.pone.0049820. PMID: 23185448.
Silva E, Osório H, Thompson G. Hepatitis C-like viruses are produced in cells from rabbit and hare DNA. Sci Rep. 2015;5:14535. doi: 10.1038/srep14535. PMID: 26416202.
Pedersen MS, Mollerup S, Nielsen LG, Jenssen H, Bukh J, Schønning K. Genome Sequence of an Unknown Subtype of Hepatitis C Virus Genotype 6: Another Piece for the Taxonomic Puzzle. Microbiol Resour Announc. 2019;8(42). doi: 10.1128/mra.01030-19. PMID: 31624172.
Pedersen MS, Fahnøe U, Madsen LW, Christensen PB, Øvrehus A, Bukh J. Characterization of a Novel Hepatitis C Virus Genotype 1 Subtype from a Patient Failing 4 Weeks of Glecaprevir-Pibrentasvir Treatment. Microbiol Resour Announc. 2021;10(41):e0075521. doi: 10.1128/mra.00755-21. PMID: 34647796.
Di H, Thor SW, Trujillo AA, Stark TJ, Marinova-Petkova A, Jones J, Wentworth DE, Barnes JR, Davis CT. Comparison of nucleic acid extraction methods for next-generation sequencing of avian influenza A virus from ferret respiratory samples. Journal of Virological Methods. 2019;270:95-105. doi: 10.1016/j.jviromet.2019.04.014.
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114-20. doi: 10.1093/bioinformatics/btu170. PMID: 24695404.
Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9(4):357-9. doi: 10.1038/nmeth.1923. PMID: 22388286; PubMed Central PMCID: PMC3322381.
Li D, Luo R, Liu CM, Leung CM, Ting HF, Sadakane K, Yamashita H, Lam TW. MEGAHIT v1.0: A fast and scalable metagenome assembler driven by advanced methodologies and community practices. Methods. 2016;102:3-11. doi: 10.1016/j.ymeth.2016.02.020. PMID: 27012178.
Buchfink B, Xie C, Huson DH. Fast and sensitive protein alignment using DIAMOND. Nature Methods. 2015;12(1):59-60. doi: 10.1038/nmeth.3176.
Jadoul M, Bieber BA, Martin P, Akiba T, Nwankwo C, Arduino JM, Goodkin DA, Pisoni RL. Prevalence, incidence, and risk factors for hepatitis C virus infection in hemodialysis patients. Kidney Int. 2019;95(4):939-47. doi: 10.1016/j.kint.2018.11.038. PMID: 30904068.
Fabrizi F, Cerutti R, Messa P. Updated Evidence on the Epidemiology of Hepatitis C Virus in Hemodialysis. Pathogens. 2021;10(9). doi: 10.3390/pathogens10091149. PMID: 34578181.
Reddy YNV, Nunes D, Chitalia V, Gordon CE, Francis JM. Hepatitis C virus infection in kidney transplantation-changing paradigms with novel agents. Hemodial Int. 2018;22 Suppl 1(Suppl 1):S53-s60. doi: 10.1111/hdi.12659. PMID: 29694721.
Khattab MA, Zakaria Y, Sadek E, Abd El Fatah AS, Fouad M, Khattab M, Moness HM, Adel NM, Ahmed E. Detection of hepatitis C virus (HCV) RNA in the peripheral blood mononuclear cells of HCV-infected patients following sustained virologic response. Clin Exp Med. 2023;23(1):131-40. doi: 10.1007/s10238-022-00791-7. PMID: 35066710.
Saad ZM, Ghany WAE, Khalifa R, Higazi A, Al-Shazly M, Said M, Keryakos H. Occult HCV infection in liver transplanted patients: frequency and consequences. Clin Exp Hepatol. 2022;8(2):125-31. doi: 10.5114/ceh.2022.115116. PMID: 36092754.
Fernández-Caso B, Fernández-Caballero J, Chueca N, Rojo E, de Salazar A, García Buey L, Cardeñoso L, García F. Infection with multiple hepatitis C virus genotypes detected using commercial tests should be confirmed using next generation sequencing. Sci Rep. 2019;9(1):9264. doi: 10.1038/s41598-019-42605-z. PMID: 31239457.
Kim KA, Lee S, Park HJ, Jang ES, Lee YJ, Cho SB, Kim YS, Kim IH, Lee BS, Chung WJ, Ahn SH, Kim S, Jeong SH. Next-generation sequencing analysis of hepatitis C virus resistance-associated substitutions in direct-acting antiviral failure in South Korea. Clin Mol Hepatol. 2023;29(2):496-509. doi: 10.3350/cmh.2022.0345. PMID: 36880209.
Huggett JF. The Digital MIQE Guidelines Update: Minimum Information for Publication of Quantitative Digital PCR Experiments for 2020. Clin Chem. 2020;66(8):1012-29. doi: 10.1093/clinchem/hvaa125. PMID: 32746458.
Kojabad AA, Farzanehpour M, Galeh HEG, Dorostkar R, Jafarpour A, Bolandian M, Nodooshan MM. Droplet digital PCR of viral DNA/RNA, current progress, challenges, and future perspectives. J Med Virol. 2021;93(7):4182-97. doi: 10.1002/jmv.26846. PMID: 33538349.