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Geographic Distribution of HCV-GT3 Subtypes and Naturally Occurring Resistance Associated Substitutions.

ABSTRACT: BACKGROUND:Little is known about the frequency or geographic distributions of naturally occurring resistance-associated substitutions (RASs) in the nonstructural protein 5A (NS5A) domain of hepatitis-C virus (HCV) genotype-3 (GT-3) different subtypes. We investigated naturally occurring GT-3 RASs that confer resistance to NS5A inhibitors. METHODS:From a publicly accessible database, we retrieved 58 complete GT-3 genomes and an additional 731 worldwide NS5A sequences from patients infected with GT-3 that were naive to direct-acting antiviral treatment. RESULTS:We performed a phylogenetic analysis of NS5A domains in complete HCV genomes to determine more precisely HCV-GT-3 subtypes, based on commonly used target regions (e.g., 5'untranslated region and NS5B partial domain). Among 789 NS5A sequences, GT-3nonA subtypes were more prevalent in Asia than in other geographic regions (P<0.0001). The A30K RAS was detected more frequently in HCV GT3nonA (84.6%) than in GT-3A subtypes (0.8%), and the amino acid change was polymorphic in isolates from Asia. CONCLUSIONS:These results provided information on the accuracy of HCV-3 subtyping with a phylogenetic analysis of the NS5A domain with data from the Los Alamos HCV genome database. This information and the worldwide geographic distribution of RASs according to HCV GT-3 subtypes are crucial steps in meeting the challenges of treating HCV GT-3.

SUBMITTER: Bagaglio S

PROVIDER: S-EPMC6410151 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Emergence and Persistence of Resistance-Associated Substitutions in HCV GT3 Patients Failing Direct-Acting Antivirals.

Project description:Background: The hepatitis C virus has a high mutation rate, which results in the emergence of resistance-associated substitutions (RASs). Despite direct-acting antivirals (DAAs) efforts to treat chronically infected HCV genotype 3 (GT3) patients, there are concerns about the emergence and persistence of RASs in DAA failures. The objective of this study was to determine the prevalence of clinically relevant RASs in HCV NS5A and NS5B regions before and after treatment to better understand the role of RASs in treatment failures. Methods: Viral RNA was extracted before and after treatment from serum samples. NS5A and NS5B regions of HCV were amplified by nested PCR, followed by Sanger sequencing. The nucleotide sequences were aligned against HCV GT3 reference sequences, and amino acid substitutions were analyzed using the geno2pheno [hcv] webserver. Results: A total of 76 patients failing DAA therapy were stratified from the cohort of 1388. RASs were detected at the baseline in 15/76 patients and at relapse in 20/76 patients with cirrhosis and previously treated with interferons. The most prevalent NS5A RAS was Y93H found in all treatment-failing patients (14/54 in DCV vs. 6/22 in VEL), followed by A62S/T and A30K. No RASs were identified in NS5B. RASs that were present at the baseline persisted through the 24-week follow-up period and were enriched with emerging RASs during the treatment. The presence of RASs may be one of the causes of treatment failures in 26.3% of patients. Amino acid substitutions were present at the baseline in most of the patients with RASs against NS5A inhibitors. Patients with the baseline Y93H and/or A30K relapse more frequently than patients harboring A62S/T. Conclusion: Treatment-failing patients harbored NS5A RASs, and the most frequent were A30K (5/20), A62S/T (20/20), and Y93H (20/20). Direct resistance testing is recommended for optimizing re-treatment strategies in treatment-failing patients.

| S-EPMC9091354 | biostudies-literature

Distribution of naturally -occurring NS5B resistance-associated substitutions in Egyptian patients with chronic Hepatitis C.

Project description:BackgroundNS5B polymerase inhibitors represent the cornerstone of the present treatment of Hepatitis C virus infection (HCV). Naturally occurring substitution mutations to NS5B inhibitors have been recorded. The current study intended to demonstrate possible natural direct acting antiviral (DAA)-mutations of the HCV NS5B region in HCV patients in Minia governorate, Egypt.MethodsSamples were collected from 27 treatment-naïve HCV patients and 8 non-responders. Out of 27 treatment-naïve patients, 17 NS5B sequences (amino acids 221-345) from treatment-naïve patients and one sample of non-responders were successfully amplified. Nucleotide sequences have been aligned, translated into amino acids, and compared to drug resistance mutations reported in the literature.ResultsNS5B amino acid sequence analysis ensures several novel NS5B mutations existence (more than 40 substitution mutations) that have not been previously documented to be correlated with a resistant phenotype. It was found that K304R (82.4%), E327D and P300T (76.5% each) substitutions were the most distributed in the tested samples, respectively. S282T, the major resistance mutation that induces high sofosbuvir-resistance level in addition to other reported mutations (L320F/C) and (C316Y/N) were not recognized. Q309R mutation is a ribavirin-associated resistance, which was recognized in one strain (5.9%) of genotype 1g sequences. Besides, one substitution mutation (E237G) was identified in the successfully amplified non-responder sample.ConclusionOur study showed various combinations of mutations in the analyzed NS5B genes which could enhance the possibility of therapy failure in patients administered regimens including multiple DAA.

| S-EPMC8049381 | biostudies-literature

Lower Rates Of Naturally Occurring Resistance-Associated Substitutions (RASs) In Hepatitis C Virus (HCV)-Infected Chronic Kidney Disease (CKD) Patients Than In HCV-Infected Patients With Only Liver Disease.

Project description:PurposeBaseline viral load and existence of resistance-associated substitutions (RASs) are associated with direct-acting antiviral agent (DAA) treatment failure in patients with chronic hepatitis C virus (HCV) infection.Patients and methodsThis study was done on HCV-infected patients with different clinical conditions, group 1 included HCV-infected patients with only liver disease (n= 24) and group 2 had HCV-infected patients with coexisting chronic kidney disease (CKD) (n =26). Baseline RAS in the viral genome, before treatment initiation, was examined in both the groups to understand the host disease status on their occurrence.ResultsPredominant genotype (gt) differed in both the groups, in group 1 it was gt3 while it was gt1 in group 2. Overall, the occurrence of RASs at baseline was seen in 10 patients (20%); in group 1 it was seen in 8 (33.3%) as compared to only 2 (7.6%) in group 2; p < 0.001. RAS in both NS5a and NS5b regions of the virus was seen in group 1 while in group 2, RASs were seen only in the NS5a region of the virus at 30K position. In group 1, multiple RASs were also seen. The existence of RAS at baseline in both the groups did not affect the attainment of post-treatment cure for the virus in terms of sustained virological response (SVR).ConclusionHost disease status influences the occurrence of baseline RAS in the virus.

| S-EPMC6878924 | biostudies-literature

Prevalence of Naturally-Occurring NS5A and NS5B Resistance-Associated Substitutions in Iranian Patients With Chronic Hepatitis C Infection.

Project description:BackgroundHepatitis C virus (HCV), non-structural 5A (NS5A), and non-structural 5B (NS5B) resistance-associated substitutions (RASs) are the main causes of failure to direct-acting antiviral agents (DAAs). NS5A and NS5B RASs can occur in patients with HCV infection naturally and before exposure to DAAs.ObjectivesThis study aimed to evaluate naturally-occurring NS5A and NS5B RASs in Iranian patients with HCV genotype 1a (HCV-1a) and -3a infections.MethodsIn this cross-sectional study, viral RNA was extracted from serum specimens. NS5A and NS5B regions were amplified using RT-PCR followed by DNA sequencing. The results of nucleotide sequences were aligned against reference sequences of HCV-1a and -3a and the amino acid substitutions were analyzed using geno2pheno [hcv] web application.ResultsAmong 135 patients with hepatitis C, NS5A amino acid substitutions/RASs were identified in 26.4% and 15.9% of patients with HCV-1a and -3a infections, respectively. The identified amino acid substitutions/RASs in the NS5A region of patients with HCV-1a infection were M28T/V/I 11.1%, Q30R/H 4.2%, L31M 1.4%, and H58Y/P/C/D/Q/S/T 16.7%. Y93H substitution was not found in HCV-1a sequences. In patients with HCV-3a infection, NS5A amino acid substitutions/RASs were A30T/K 9.5%, L31F 1.6%, P58S/T/C 3.2%, Y93H 3.2%, and Y93N 3.2%. No resistance substitutions were identified in NS5B sequences from patients with HCV-1a and -3a infections.ConclusionIn this study, baseline amino acid substitutions/RASs were only identified in the NS5A region in Iranian patients with HCV-1a and -3a infections, and the prevalence of these amino acid substitutions/RASs were in accordance with similar studies. There were no RASs in the HCV-1a and -3a NS5B region.

| S-EPMC7876467 | biostudies-literature

Naturally Occurring Resistance-Associated Variants to Hepatitis C Virus Direct-Acting Antiviral Agents in Treatment-Naive HCV Genotype 6a-Infected Patients.

Project description:Background and objectiveThe direct-acting antiviral agents (DAAs) antiviral therapy has drastically improved the prognosis of hepatitis C virus (HCV) patients. However, the viral drug resistance-associated variants (RAVs) can limit the efficacy of DAAs. For the HCV-6a is not the predominant prevalent genotype; the data on the prevalence of naturally occurring RAVs in it is scarce. Our study aims to assess the prevalence of RAVs in treatment-naive HCV-6a patients.MethodsNested PCR assays were performed on 95 HCV-6a patients to amplify HCV viral regions of NS3, NS5A, and NS5B.ResultsIn NS3/4A region, we detected Q80K in 95.5% isolates (84/88) and D168E in 2.3% isolates (2/88). In NS5A region, we detected Q30R in 93.2% isolates (82/88), L31M in 4.6% isolates (4/88), and H58P in 6.8% isolates (6/88). In NS5B region, we detected A15G in 2.3% isolates (2/88), S96T in 1.1% isolates (1/88), and S282T in 20.7% isolates (17/88) and we detected I482L in 100% isolates (4/4), V494A in 50% isolates (2/4), and V499A in 100% isolates (4/4).ConclusionsRAVs to DAAs preexist in treatment-naive HCV-6a patients. Further studies should address the issue of the impact of RAVs in response to DAA therapies for HCV-6a patients.

| S-EPMC5661091 | biostudies-literature

Compartmentalization of Resistance-Associated Substitutions in HIV/HCV-Infected Patients: Possible Correlation with Infecting HCV Genotype.

Project description:Resistance-associated substitutions (RASs) may exist prior to treatment and contribute to the failure of treatment with direct-acting antivirals (DAAs). As the major site of HCV replication, naturally occurring variants with RASs may segregate into the liver. In the present study, we performed viral population sequencing to retrospectively investigate the NS3 and NS5A RAS profiles in 34 HIV/HCV coinfected patients naïve to anti-HCV treatment who underwent diagnostic liver biopsy between 2000 and 2006 and had liver and plasma samples available. Sixteen were infected by HCV genotype (GT) 1a, 11 by GT3a, and 7 by GT4d. The analysis of the NS3 domain in GT1a showed a difference in strain between the liver and plasma in three cases, with a preponderance of specific RASs in the liver compartment. In GT4d samples, 6/7 coupled liver and plasma samples were concordant with no RASs. Sequence analysis of the NS5A domain showed the presence of RASs in the livers of 2/16 patients harboring GT1a but not in the corresponding plasma. In GT4d, NS5A RASs were detected in 7/7 liver tissues and 5/7 plasma samples. NS3 domain and NS5A domain were found to be conserved in plasma and livers of patients infected with GT3a. Thus, RASs within GT1a and GT4d more likely segregate into the liver and may explain the emergence of resistant strains during DAA treatment.

| S-EPMC8402799 | biostudies-literature

Naturally occurring mutations associated with resistance to HCV NS5B polymerase and NS3 protease inhibitors in treatment-naive patients with chronic hepatitis C.

Project description:The detection of baseline resistance mutations to new direct-acting antivirals (DAAs) in HCV chronically infected treatment-naïve patients could be important for their management and outcome prevision. In this study, we investigated the presence of mutations, which have been previously reported to be associated with resistance to DAAs in HCV polymerase (NS5B) and HCV protease (NS3) regions, in sera of treatment-naïve patients.HCV RNA from 152 naïve patients (84 % Italian and 16 % immigrants from various countries) infected with different HCV genotypes (21,1a; 21, 1b; 2, 2a; 60, 2c; 22, 3a; 25, 4d and 1, 4k) was evaluated for sequence analysis. Amplification and sequencing of fragments in the NS5B (nt 8256-8640) and NS3 (nt 3420-3960) regions of HCV genome were carried out for 152 and 28 patients, respectively. The polymorphism C316N/H in NS5B region, associated with resistance to sofosbuvir, was detected in 9 of the 21 (43 %) analysed sequences from genotype 1b-infected patients. Naturally occurring mutations V36L, and M175L in the NS3 protease region were observed in 100 % of patients infected with subtype 2c and 4.A relevant proportion of treatment naïve genotype 1b infected patients evaluated in this study harboured N316 polymorphism and might poorly respond to sofosbuvir treatment. As sofosbuvir has been approved for treatment of HCV chronic infection in USA and Europe including Italy, pre-treatment testing for N316 polymorphism on genotype 1b naïve patients should be considered for this drug.

| S-EPMC4650141 | biostudies-literature

Naturally occurring mutations to HCV protease inhibitors in treatment-naive patients.

Project description:BACKGROUND: Protease inhibitors (PIs) to treat hepatitis C (HCV) virus infection have been approved and others are under development. RESULTS: The aims of this study were to illustrate natural polymorphisms in the HCV protease and measure the frequency of PI resistance mutations in different HCV genotypes from PI-naïve patients.Direct sequencing of HCV NS3/4A protease was performed in 156 HCV patients naïve to PIs who were infected with genotype 1a (n = 31), 1b (n = 39), 2 (n = 30), 3 (n = 33) and 4 (n = 23).Amino acid (aa) substitutions associated with HCV PI resistance were found in 17/156 (10.8%) sequences. Mutations V36L, T54S, V55A/I, and Q80K/L were observed in 29% of patients with genotype 1a, and V55F, Q80L/N and M175L in 10% of patients with genotype 1b. The mutation V158M was found in 3% of patients with genotype 2, D168Q was present in 100% of patients with genotype 3 and D168E was observed in 13% of patients with genotype 4. In addition, multiple aa polymorphisms not associated with PI resistance were detected in patients with genotypes 1a, 1b and 4. CONCLUSIONS: Although major PI resistance mutations were not detected, other resistance mutations conferring low level resistance to PIs together with a number of natural polymorphisms were observed in proteases of PI naïve HCV patients. A more extensive analysis is needed to better evaluate the impact of baseline resistance and compensatory mutations in the efficacy of HCV PI treatment.

| S-EPMC3493344 | biostudies-literature

Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naive patients.

Project description:BackgroundDirect-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. However, selection of DAA-resistant viral variants may hamper treatment. The aim of this study was to illustrate potential natural DAA-resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naïve patients.MethodsDirect sequencing of HCV NS5A and NS5B regions was performed in 32 patients infected with HCV genotype 1a and 30 patients infected with HCV genotype 1b; all subjects were naïve to DAAs.ResultsIn genotype 1a strains, resistance mutations in NS5A (M28V, L31M and H58P) were observed in 4/32 (12.5%) patients, and resistance mutations in NS5B (V321I, M426L, Y448H, Y452H) were observed in 4/32 (12.5%) patients. In genotype 1b, resistance mutations in NS5A (L28V, L31M, Q54H, Y93H and I280V) were observed in 16/30 (53.3%) patients, while resistance mutations in NS5B (L159F, V321I, C316N, M426L, Y452H, R465G and V499A) were observed in 27/30 (90%) patients.ConclusionsMutations conferring DAA resistance were detected in NS5A and NS5B of HCV genotypes 1a and 1b from DAA-naïve patients. Although some mutations confer only a low level of resistance, the presence at baseline of mutated HCV variants should be taken into consideration in the context of DAA therapy.

| S-EPMC3878512 | biostudies-literature

Naturally occurring drug resistance associated variants to hepatitis C virus direct-acting antiviral agents in treatment-naive HCV genotype 1b-infected patients in China.

Project description:The direct-acting antiviral agents (DAAs) have drastically improved the prognosis of hepatitis C virus (HCV) patients. However, the resistance-associated variants (RAVs) to DAAs may hamper treatment. There was a lack of data on the prevalence of pre-exist RAVs in Chinese HCV-infected patients. We performed nested PCR assays on 74 HCV genotype 1b-infected patients to amplify HCV viral regions of NS3, NS5A, and NS5B to investigate the prevalence of RAVs to DAAs in treatment-naive HCV genotype1b-infected patients in China. The mutations A156S, T54S, and D168Y of the NS3/4A region were found in 18.33% (11/60), 6.67% (4/60), and 1.67% (1/60) of the successfully amplified cases. Mutations Q30R, L31M, and H58P of the NS5A region were confirmed in 57.63% (34/59), 1.69%(1/59), and 86.44% (51/59) of the cases. Mutations C316N, S365A, M414L, M423I, Y448H, I482T, I482 V, V494L, P495S, and V499A of the NS5B region were detected in 100% (60/60), 3.33% (2/60), 5.88% (3/51), 1.96% (1/51), 1.96% (1/51), 5.88% (3/51), 1.96% (1/51), 3.92% (2/51), 5.88% (3/51), and 15.69% (8/51) of cases, respectively. Naturally occurring RAVs to DAAs pre-exist in treatment-naive Chinese HCV genotype 1b-infected patients and the characteristic is different from that in Europe and the United States. Clinicians should consider RAVs upon the introduction of DAA-based antiviral therapy.

| S-EPMC5428597 | biostudies-literature

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