Baseline quasispecies selection and novel mutations contribute to emerging resistance-associated substitutions in hepatitis C virus after direct-acting antiviral treatment.
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ABSTRACT:
SUBMITTER: Kai Y
PROVIDER: S-EPMC5278351 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF + DCV ± ribavirin (RBV) or SOF + peginterferon (PEG) + RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF + DCV ± RBV group and 80.0% for the SOF + PEG + RBV arm. Cirrhosis, prior treatment with interferon/PEG + RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.
| S-EPMC9706524 | biostudies-literature
Project description:Background & aimsWe aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections.MethodsA total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing.ResultsFailure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens.ConclusionsFailure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV.Lay summaryResistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
| S-EPMC7424232 | biostudies-literature
Project description:Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno-and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0-48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients' characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.
| S-EPMC8781716 | biostudies-literature
Project description:Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on-therapy biopsies, 408 genes (±1.2-fold, P < 0.01) were differentially expressed. Genes down-regulated on treatment were predominantly ISGs. Down-regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy.
| S-EPMC6204120 | biostudies-literature
Project description:Background:Direct-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 methods:HD and RTx patients infected with HCV-genotype 1 (GT1) were subjected to sequencing of the NS3, NS5A and NS5B regions. Results:Direct 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). Conclusion:The 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.
| S-EPMC6208931 | biostudies-literature
Project description:BackgroundDirect-acting antivirals (DAAs) against hepatitis C virus (HCV) are potent and highly efficacious. However, resistance-associated substitutions (RASs) relevant to DAAs can impair treatment effectiveness even at baseline. Moreover, the prevalence of baseline RASs in HCV genotype 1b-infected patients in western China is still unclear.Materials and methodsDirect sequencing of the HCV NS3, NS5A, and NS5B regions was performed in baseline serum samples of 70 DAAs treatment-naïve HCV 1b-infected patients in western China. The sequences were analyzed with MEGA version 5.05 software. Evolutionary patterns of RASs and amino-acid covariance patterns in the NS3, NS5A, and NS5B genes were analyzed by MEGA and Cytoscape (version 3.2.1), respectively.ResultsThe presence of at least one RAS in the NS3 region (C16S, T54S, Q80R/L, A87T, R117H, S122G, V132I, V170I) was observed in 85.48% (53 of 62) of patients, RASs in the NS5A region (L28M, R30Q, Q54H, P58S/T, Q62H/R, Y93H) were observed in 42.42% (28 of 66) of patients, and RASs in the NS5B region (N142S, A300T, C316N, A338V, S365A, L392I, M414L, I424V, A442T, V499A, S556G) were observed in 100% (44 of 44) of patients. Evolutionary patterns of RASs and amino-acid covariance patterns for the NS3, NS5A, and NS5B genes are reported.ConclusionThe prevalence of RASs relevant to DAAs detected in the NS3, NS5A, and NS5B regions of HCV 1b from DAA treatment-naïve patients is high. Therefore, more attention should be paid to RASs associated with DAAs in the upcoming DAA-treatment era in China.
| S-EPMC5673042 | biostudies-literature
Project description:We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.
| S-EPMC5454875 | biostudies-literature
Project description:ImportanceRecent reports based on the US Food and Drug Administration's voluntary Adverse Events Reporting System raised questions about the safety of direct-acting antivirals (DAAs) for treatment of the hepatitis C virus (HCV).ObjectiveTo assess the rates of adverse events in patients with HCV infection exposed to DAAs compared with those not exposed.Design, setting, and participantsA retrospective cohort study calculated unadjusted adverse event rates for exposed vs unexposed time, using claims and clinical data from 3 health systems between January 1, 2012, and December 31, 2017. Of 82 419 eligible adults, a total of 33 808 who met eligibility criteria (age, 18-88 years; HCV quantitative result or genotype from 2012 or later; continuously enrolled; naive to DAA treatment at baseline) were included. Marginal structural modeling methods were used to adjust time-to-event analyses for characteristics that are associated with both outcomes and probability of treatment.Interventions or exposuresExposure to DAAs compared with no DAA exposure.Main outcomes and measuresDeath, multiple organ failure, liver cancer, hepatic decompensation, acute-on-chronic liver event, acute myocardial infarction, ischemic or hemorrhagic stroke, arrhythmia, acute kidney failure, nonliver cancer, hepatitis B reactivation, hospitalizations, and emergency department visits.ResultsOf the 33 808 patients who met all inclusion criteria, 20 899 (61.8%) were men; mean (SD) age was 57.2 (10.6) years. In unadjusted analyses, DAA exposure was associated with significantly lower rates of death (10.7 vs 33.7 events per 1000 person-years; rate ratio [RR], 0.32, 95% CI, 0.25-0.40). Seven other unadjusted adverse clinical events ratios were below 70% and statistically significant favoring the DAA group: multiple organ failure (RR, 0.56; 95% CI, 0.44-0.72), liver cancer (RR, 0.62; 95% CI, 0.48-0.80), hepatic decompensation (RR, 0.62; 95% CI, 0.52-0.73), acute-on-chronic liver event (RR, 0.68; 95% CI, 0.56-0.84), acute myocardial infarction (RR, 0.64; 95% CI, 0.42-0.97), ischemic stroke (RR, 0.63; 95% CI, 0.42-0.95), and hemorrhagic stroke (RR, 0.47; 95% CI, 0.25-0.89); none favored the non-DAA group. In the marginal structural modeling-adjusted analysis, DAA exposure was associated with statistically significant lower odds of adverse events than non-DAA exposure for death (adjusted odds ratio [aOR], 0.42; 95% CI, 0.30-0.59), multiple organ failure (aOR, 0.67; 95% CI, 0.49-0.90), hepatic decompensation (aOR, 0.61; 95% CI, 0.49-0.76), acute-on-chronic liver event (aOR, 0.71; 95% CI, 0.56-0.91), and arrhythmia (aOR, 0.47; 95% CI, 0.25-0.88).Conclusions and relevanceDirect-acting antiviral exposure may not be associated with higher rates of any serious adverse events, including those related to liver, kidney, and cardiovascular systems. Safety concerns based on previous reports did not appear to be supported in this study with more comprehensive data and rigorous statistical methods.
| S-EPMC6563580 | biostudies-literature
Project description:We previously revealed that Angiopoietin-2 (Ang2) predicts non-regression of liver fibrosis based on liver stiffness measurement (LSM) at 24 weeks after anti-hepatitis C virus (HCV) treatment. In this study, we extended the observational period to 96 weeks to investigate the factors associated with non-regression after treatment with direct-acting-antivirals (DAAs). Patients treated with DAAs who underwent transient elastography at baseline and 24 and 96 weeks after DAA therapy were included. Baseline and post-treatment serum Ang2 levels were measured. Liver fibrosis stages were defined based on LSM. Multivariate regression was used to evaluate factors associated with non-regression of liver fibrosis between various time points. In total, 110 patients were included. Of these, 11% showed non-regression of LSM-based fibrosis stage at 96 weeks after DAA therapy. In multivariate analysis, advanced liver fibrosis stage and high baseline Ang2 levels were significantly associated with non-regression at 96 weeks. In patients with advanced liver fibrosis (F3/4), baseline Ang2 levels were associated with non-regression of liver fibrosis stage. Between SVR24 and SVR96, post-treatment Ang2 levels and controlled attenuation parameter values at SVR24 were significantly associated with non-regression of liver fibrosis stage in patients with F3/4. Thus, serum Ang2 levels are an important target for monitoring and therapy.
| S-EPMC8080679 | biostudies-literature
Project description:With the introduction of direct-acting antiviral (DAA) agents, hepatitis C virus (HCV) treatment has dramatically improved. However, there are insufficient data on the benefits of DAA therapy in hepatocellular carcinoma (HCC). The purpose of this study was to investigate the outcome of patients who received DAA therapy after HCC treatment. We retrospectively reviewed patients with HCV-related HCC in a single medical center, and the outcome of patients with or without DAA therapy was analyzed. In total, 107 HCC patients were enrolled, of whom 60 had received DAA therapy after treatment for HCC. There were no significant intergroup differences in age, sex, laboratory results, or tumor burden. A more advanced stage was noted in the no DAA group (P = 0.003). In the treatment modality, sorafenib was commonly prescribed in the no DAA group (P = 0.007). The DAA group had a longer overall survival (OS) time than the no DAA group (P<0.001). When stratified by Barcelona Clinic Liver Cancer staging, the DAA group had better OS in the HCC stages 0-A and B-C (P = 0.034 and P = 0.006). There were 35 patients who received DAA therapy after curative HCC therapy. At a median follow-up of 20 months, 37.1% patients had HCC recurrence after DAA therapy. There was no statistical difference in recurrence-free survival between patients receiving and those not receiving DAA (P = 0.278). DAA therapy improved the survival outcome of HCC patients and did not increase recurrent HCC after curative therapy.?.
| S-EPMC7244104 | biostudies-literature