title: Prevalence of naturally occurring protease inhibitor resistance-associated variants in hemodialysis and renal transplant patients with hepatitis C virus infection.
abstract: Background NS3 protease inhibitors (PIs) were the first direct antiviral agents used for the treatment of hepatitis C virus. The combination of second-wave PIs with other direct antiviral agents enabled the use of interferon-free regimens for chronic kidney disease patients on dialysis and renal transplant (RTx) recipients, populations in which the use of interferon and ribavirin is limited. However, the occurrence of PI resistance-associated variants (RAVs), both baseline and induced by therapy, has resulted in the failure of many treatment strategies. Methods The aim of this study was to estimate the prevalence of PI RAVs and of the Q80K polymorphism in chronic kidney disease patients on hemodialysis and RTx recipients. Direct sequencing of the NS3 protease was performed in 67 patients (32 hemodialysis and 35 RTx).Results RAVs to PIs were detected in 18% of the patients: V55A (9%), V36L (1.5%), T54S (1.5%), S122N (1.5%), I170L (1.5%), and M175L (1.5%). Only 1.5% of the patients carried the Q80K polymorphism. The frequency of these mutations was more than two times higher in patients infected with GT1a (25%) than GT1b (9.7%) (P=0.1). The mutations were detected in 20% of treatment-naive patients and in 15.6% of peginterferon/ribavirin-experienced patients (P=0.64). Furthermore, no mutation that would confer high resistance to PIs was detected.Conclusion The Q80K polymorphism was rare in the population studied. The occurrence of RAVs was common, with predominance in GT1a. However, the variants observed were those associated with a low level of resistance to PIs, facilitating the use of these drugs in this special group of patients.
authors.affiliation: aGastroenterology Division, Federal University of Sao Paulo bAlbert Einstein Medicina Diagnóstica, Hospital Israelita Albert Einstein cDepartment of Gastroenterology, School of Medicine, Laboratory of Tropical Gastroenterology and Hepatology 'João Alves de Queiroz and Castorina Bittencourt Alves', LIM-07, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Rita C F
authors.initials: RCF
authors.lastname: Tavares
authors.forename: Ana C C A
authors.initials: ACCA
authors.lastname: Feldner
authors.forename: João R R
authors.initials: JRR
authors.lastname: Pinho
authors.forename: Silvia N O
authors.initials: SNO
authors.lastname: Uehara
authors.forename: Christini T
authors.initials: CT
authors.lastname: Emori
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Carvalho-Filho
authors.forename: Ivonete S S
authors.initials: ISS
authors.lastname: Silva
authors.forename: Rúbia A F
authors.initials: RAF
authors.lastname: Santana
authors.forename: Vanessa F D
authors.initials: VFD
authors.lastname: de Castro
authors.forename: Gregório T F
authors.initials: GTF
authors.lastname: Castoli
authors.forename: Charliana U
authors.initials: CU
authors.lastname: Cristovão
authors.forename: Maria L C G
authors.initials: MLCG
authors.lastname: Ferraz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001938:Brazil / Q000453:epidemiology; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology* / Q000821:virology; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D010641:Phenotype; D011110:Polymorphism, Genetic; D015995:Prevalence; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000453:epidemiology / Q000628:therapy*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases