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Hepatitis C Virus Deletion Mutants Are Found in Individuals Chronically Infected with Genotype 1 Hepatitis C Virus in Association with Age, High Viral Load and Liver Inflammatory Activity.

Cheroni C, Donnici L, Aghemo A, Balistreri F, Bianco A, Zanoni V, Pagani M, Soffredini R, D'Ambrosio R, Rumi MG, Colombo M, Abrignani S, Neddermann P, De Francesco R - PLoS ONE (2015)

Bottom Line: HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%).Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver.While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.

View Article: PubMed Central - PubMed

Affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.

ABSTRACT
Hepatitis C virus (HCV) variants characterized by genomic deletions in the structural protein region have been sporadically detected in liver and serum of hepatitis C patients. These defective genomes are capable of autonomous RNA replication and are packaged into infectious viral particles in cells co-infected with the wild-type virus. The prevalence of such forms in the chronically HCV-infected population and the impact on the severity of liver disease or treatment outcome are currently unknown. In order to determine the prevalence of HCV defective variants and to study their association with clinical characteristics, a screening campaign was performed on pre-therapy serum samples from a well-characterized cohort of previously untreated genotype 1 HCV-infected patients who received treatment with PEG-IFNα and RBV. 132 subjects were successfully analyzed for the presence of defective species exploiting a long-distance nested PCR assay. HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%). Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver. While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.

No MeSH data available.


Related in: MedlinePlus

Virogical responses to PEG-IFNα/RBV stratified for HCV defective forms or IL28B genotype.RVR, EVR, ETR and SVR rates in the overall population as well as relapse rates in ETR-positive subjects, according to the presence of HCV deletions (A-B) or IL28B genotype (C-D), are reported. The presence of HCV defective particles does not have a significant effect on RVR, EVR, ETR or SVR rates, while it correlates with a higher probability of relapse in ETR-positive subjects (A-B). IL28B CT/TT genotypes are significantly associated with lower RVR, EVR, ETR and SVR rates and correlate with a higher probability of relapse (C-D).
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pone.0138546.g002: Virogical responses to PEG-IFNα/RBV stratified for HCV defective forms or IL28B genotype.RVR, EVR, ETR and SVR rates in the overall population as well as relapse rates in ETR-positive subjects, according to the presence of HCV deletions (A-B) or IL28B genotype (C-D), are reported. The presence of HCV defective particles does not have a significant effect on RVR, EVR, ETR or SVR rates, while it correlates with a higher probability of relapse in ETR-positive subjects (A-B). IL28B CT/TT genotypes are significantly associated with lower RVR, EVR, ETR and SVR rates and correlate with a higher probability of relapse (C-D).

Mentions: We next examined the correlation between the presence of defective HCV forms and clinical characteristics in the study cohort. As illustrated in Table 1, by univariate analysis, the presence of HCV defective genomes was found to be significantly associated with patient older age (Wilcoxon test Pval 0.0367), higher viral load (Wilcoxon test Pval 0.0046) and with mild to severe hepatic necroinflammatory activity (histological activity index ≥ 9; Fisher’s test Pval 0.003). Analyzing viral kinetics during PEG-IFNα/RBV treatment, we could not detect substantial differences in the decline of viral load at early time-points (RVR and cEVR rates) in carriers of HCV deleted variants; also ETR percentages were unchanged. SVR rates were lower for patients with defective genomes (24% compared to 38.3%), but the difference was not found to be statistically significant (Fisher test Pval 0.247, Fig 2A). Notably, however, among 74 patients who were HCV RNA-negative at the end of the treatment, virological relapse was observed in 60% (9/15) of the subjects carrying HCV defective genomes compared to 30% (18/59) of those infected with only the full-length virus (Fig 2B). The potential association between virological relapse and the presence of HCV defective genomes is characterized by a strong odds ratio (OR 3.35) but displayed no statistical significance by univariable analysis (Chi-test Pval 0.034, Fisher’s test Pval 0.069). This association, however, was found to be significant in a multivariate analysis that included the effect of patient IL28B genotype (see below).


Hepatitis C Virus Deletion Mutants Are Found in Individuals Chronically Infected with Genotype 1 Hepatitis C Virus in Association with Age, High Viral Load and Liver Inflammatory Activity.

Cheroni C, Donnici L, Aghemo A, Balistreri F, Bianco A, Zanoni V, Pagani M, Soffredini R, D'Ambrosio R, Rumi MG, Colombo M, Abrignani S, Neddermann P, De Francesco R - PLoS ONE (2015)

Virogical responses to PEG-IFNα/RBV stratified for HCV defective forms or IL28B genotype.RVR, EVR, ETR and SVR rates in the overall population as well as relapse rates in ETR-positive subjects, according to the presence of HCV deletions (A-B) or IL28B genotype (C-D), are reported. The presence of HCV defective particles does not have a significant effect on RVR, EVR, ETR or SVR rates, while it correlates with a higher probability of relapse in ETR-positive subjects (A-B). IL28B CT/TT genotypes are significantly associated with lower RVR, EVR, ETR and SVR rates and correlate with a higher probability of relapse (C-D).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4583497&req=5

pone.0138546.g002: Virogical responses to PEG-IFNα/RBV stratified for HCV defective forms or IL28B genotype.RVR, EVR, ETR and SVR rates in the overall population as well as relapse rates in ETR-positive subjects, according to the presence of HCV deletions (A-B) or IL28B genotype (C-D), are reported. The presence of HCV defective particles does not have a significant effect on RVR, EVR, ETR or SVR rates, while it correlates with a higher probability of relapse in ETR-positive subjects (A-B). IL28B CT/TT genotypes are significantly associated with lower RVR, EVR, ETR and SVR rates and correlate with a higher probability of relapse (C-D).
Mentions: We next examined the correlation between the presence of defective HCV forms and clinical characteristics in the study cohort. As illustrated in Table 1, by univariate analysis, the presence of HCV defective genomes was found to be significantly associated with patient older age (Wilcoxon test Pval 0.0367), higher viral load (Wilcoxon test Pval 0.0046) and with mild to severe hepatic necroinflammatory activity (histological activity index ≥ 9; Fisher’s test Pval 0.003). Analyzing viral kinetics during PEG-IFNα/RBV treatment, we could not detect substantial differences in the decline of viral load at early time-points (RVR and cEVR rates) in carriers of HCV deleted variants; also ETR percentages were unchanged. SVR rates were lower for patients with defective genomes (24% compared to 38.3%), but the difference was not found to be statistically significant (Fisher test Pval 0.247, Fig 2A). Notably, however, among 74 patients who were HCV RNA-negative at the end of the treatment, virological relapse was observed in 60% (9/15) of the subjects carrying HCV defective genomes compared to 30% (18/59) of those infected with only the full-length virus (Fig 2B). The potential association between virological relapse and the presence of HCV defective genomes is characterized by a strong odds ratio (OR 3.35) but displayed no statistical significance by univariable analysis (Chi-test Pval 0.034, Fisher’s test Pval 0.069). This association, however, was found to be significant in a multivariate analysis that included the effect of patient IL28B genotype (see below).

Bottom Line: HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%).Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver.While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.

View Article: PubMed Central - PubMed

Affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.

ABSTRACT
Hepatitis C virus (HCV) variants characterized by genomic deletions in the structural protein region have been sporadically detected in liver and serum of hepatitis C patients. These defective genomes are capable of autonomous RNA replication and are packaged into infectious viral particles in cells co-infected with the wild-type virus. The prevalence of such forms in the chronically HCV-infected population and the impact on the severity of liver disease or treatment outcome are currently unknown. In order to determine the prevalence of HCV defective variants and to study their association with clinical characteristics, a screening campaign was performed on pre-therapy serum samples from a well-characterized cohort of previously untreated genotype 1 HCV-infected patients who received treatment with PEG-IFNα and RBV. 132 subjects were successfully analyzed for the presence of defective species exploiting a long-distance nested PCR assay. HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%). Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver. While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.

No MeSH data available.


Related in: MedlinePlus