Prevalence of resistance-associated substitutions to direct-acting antiviral agents in hemodialysis and renal transplant patients infected with hepatitis C virus

Abstract

BackgroundDirect-acting antiviral agents (DAAs) permit the use of interferon (IFN)-free regimens to treat hepatitis C (HCV) in patients with chronic kidney disease (CKD) on hemo-dialysis (HD) or renal transplant (RTx) recipients, with excellent response rates and safety. However, the occurrence of basal or therapy-induced resistance-associated substitutions (RASs) to DAAs can result in treatment failure. The aim of this study was to estimate the prevalence of RASs to NS3A, NS5A and NS5B inhibitors, and particularly the Q80K polymorphism, in CKD patients on HD and RTx recipients infected with HCV.Patients and methodsHD and RTx patients infected with HCV-genotype 1 (GT1) were subjected to sequencing of the NS3, NS5A and NS5B regions.ResultsDirect sequencing of NS3 protease, NS5A and NS5B was performed in 76 patients (HD, n=37; RTx, n=39). The overall prevalence of RASs was 38.2%, but only 5.3% of the patients had mutations in more than one region. Substitutions were detected in NS3A (17.8%), NS5A (21.9%) and NS5B (8.4%). Q80K was detected in 1.5 % of the patients. Highly inhibitory RASs were uncommon (L31M, 2.6%; L159F+C316N, 2.6%). RASs were more prevalent in HCV-GT1a (42.9%) than in HCV-GT1b (32.4%), P=0.35. RASs were detected in 52.4% of treatment-naive patients and 27.8% of peg-IFN/ribavirin-experienced patients (P=0.12). The presence of RASs was associated with time of RTx (P=0.01).ConclusionThe Q80K polymorphism was uncommon in our sample of HD and RTx patients. Despite the high prevalence of naturally occurring RASs, most of the substitutions detected were associated with a low level of resistance to DAAs.

Infectious Complications Following Kidney Transplantation—A Focus on Hepatitis C Infection, Cytomegalovirus Infection and Novel Developments in the Gut Microbiota

“…Resistance may occur particularly when therapeutics levels are suboptimal, thus creating selective pressure for resistant HCV to emerge as the dominant species [45]. A study undertaken in Brazil involving 76 patients, of whom 39 were kidney transplant recipients and 37 were on chronic haemodialysis, examined the prevalence of resistance-associated substitutions to DAAs and found that the overall prevalence of resistance was 38.2% with substitution resistance detected in NS3A (17.8%), NS5A (21.9%) and NS5B (8.4%) inhibitors [46]. Resistance substitutions were higher in Genotype 1a (42.9%) compared with Genotype 1b (32.4%) ( p = 0.35) [46].…”

“…A study undertaken in Brazil involving 76 patients, of whom 39 were kidney transplant recipients and 37 were on chronic haemodialysis, examined the prevalence of resistance-associated substitutions to DAAs and found that the overall prevalence of resistance was 38.2% with substitution resistance detected in NS3A (17.8%), NS5A (21.9%) and NS5B (8.4%) inhibitors [46]. Resistance substitutions were higher in Genotype 1a (42.9%) compared with Genotype 1b (32.4%) ( p = 0.35) [46]. However, this study was limited by the fact that patients were restricted to Genotype 1 and the sample size was small.…”

In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment

“…New generation of highly effective interferon-free, direct-acting antiviral (DAA) therapies have revolutionized the care of HCV-infected individuals due to their dramatically high cure rate (Hezode, 2018). However, the low access to this new generation of drugs in low income countries, the detection in few patients of occult HCV infection (Attar and Van Thiel, 2015; Elmasry et al, 2017) and the emergence of drug resistance and suboptimal activity toward some genotypes (Sun et al, 2018; Tavares et al, 2018) occasionally reported in DAA-treated subjects could threaten the achievement of HCV eradication in the absence of an effective vaccine.…”