Impact of NS5A Sequences of Hepatitis C Virus Genotype 1a on Early Viral Kinetics during Treatment with Peginterferon‐α2a plus Ribavirin

Pero, Francesca Dal; Tang, Kwok; Gerotto, Martina; Bortoletto, Gladis; Paulon, Emma; Herrmann, Eva; Zeuzem, Stefan; Alberti, Alfredo; Naoumov, Nikolai V.

doi:10.1086/521306

Cited by 16 publications

(14 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it was observed that the change from isoleucin to valine at position 2252, as compared to the consensus sequence, was positively correlated with a sustained viral response. Similarly, the variability in the V3 region was associated with a sustained viral response, as already reported by others [Murphy et al, 2002;Dal Pero et al, 2007;Jardim et al, 2008]. A significantly higher number of mutations was Fig.…”

Section: Discussionsupporting

confidence: 78%

Mutations in the E2 and NS5A regions in patients infected with hepatitis C virus genotype 1a and their correlation with response to treatment

Yahoo

Sabahi

Shahzamani

et al. 2011

Journal of Medical Virology

View full text Add to dashboard Cite

Heterogeneity of subgenomic regions of hepatitis C virus (HCV) may be associated with response to interferon (IFN) therapy. The amino acid sequences of the PKR/eIF-2α phosphorylation homology domain (pePHD), IFN sensitivity determining region (ISDR), PKR binding domain (PKRBD), and variable region 3 (V3) were studied in 19 patients before and after 4 weeks of treatment. All patients were infected with HCV genotype 1a and were treated with pegylated-IFN and ribavirin. Thirteen patients achieved sustained viral response (responders) and six failed to clear viral RNA (nonresponders). The amino acid sequences in the pePHD and ISDR were identical in responders and nonresponders. However, amino acid substitution at position 2252 of PKRBD was significantly different between responders and nonresponders (P = 0.044). A larger number of mutations were observed in the V3 region of responders (P < 0.001). In this region, the amino acid in position 2364 differed between responders and nonresponders (responders: aspartic acid and serine, nonresponders: asparagine, P = 0.018). The amino acid sequences in the regions which were studied did not change after 4 weeks of treatment. It is concluded that the presence of specific amino acids in position 2252 of PKRBD and position 2364 of V3 might be associated with clinical response to IFN.

show abstract

Section: Discussionsupporting

confidence: 78%

Mutations in the E2 and NS5A regions in patients infected with hepatitis C virus genotype 1a and their correlation with response to treatment

Yahoo

Sabahi

Shahzamani

et al. 2011

Journal of Medical Virology

View full text Add to dashboard Cite

show abstract

“…To date, the most likely causes for therapeutic failure are non-compliance, insufficient drug levels or dose reductions, drug toxicity, and interruptions in therapy–not resistant, escape variants [85], [86]. In fact, a study of the sequence variability in the NS5A gene during treatment found no selection of interferon resistant HCV strains [87]. Another study of the full length polyprotein also found no significant difference in the number of mutations between non-responders and relapsers [88].…”

Section: Discussionmentioning

confidence: 99%

The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

2009

View full text Add to dashboard Cite

BackgroundPatients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV–a virus that is at least hundreds of years old–one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system.Methods and FindingsWe have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR).ConclusionAn evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.

show abstract

“…In our study, the higher level of serum adiponectin in patients with genotype 2a was demonstrated when compared with that in patients with genotype 1b. It is well known that clinical features and treatment response of CHC are partly determined by several viral factors, including genotype [40][41][42][43]. Among them are viral genotype 1 and high viral load correlated with more necroinflammatory activity, rapid progression of liver disease, and a poor response to antiviral therapy [40,41].…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that clinical features and treatment response of CHC are partly determined by several viral factors, including genotype [40][41][42][43]. Among them are viral genotype 1 and high viral load correlated with more necroinflammatory activity, rapid progression of liver disease, and a poor response to antiviral therapy [40,41]. Genotype 2, in contrast, might be directly involved in the development of hepatic steatosis in patients with chronic HCV infection [39].…”

Section: Discussionmentioning

confidence: 99%

Serum Level of Adiponectin Correlated with Gender and Genotype in Patients with Chronic Hepatitis C

et al. 2008

View full text Add to dashboard Cite

Adiponectin is well recognized as plasma physiologically active polypeptide hormone exclusively derived from human and animal mature adipocytes, with vigorous property in antidiabetic, antiobesity, antiatherogenic, and anti-inflammatory processes. In this study, we investigated the correlation between serum adiponectin level and clinical and pathological parameters in patients with chronic hepatitis C (CHC). The study included 127 patients with CHC and 42 healthy volunteers as controls whose laboratory parameters and serum adiponectin and tumor necrosis factor-alpha (TNF-alpha) were assessed using enzyme-linked immunosorbent assay (ELISA). We demonstrated that a lower serum adiponectin level was associated with male gender, higher gamma-glutamyltransferase (gamma-GGT), higher albumin, higher TNF-alpha, and steatosis grade. The higher level of serum adiponectin in patients with genotype 2a was demonstrated when compared with that in the patients with genotype 1b. Furthermore, of great interest, results suggested that the significant differences regarding viral genotype seemed to occur only in male patients with CHC but not in female patients. In conclusion, serum adiponectin was associated with gender, genotype, liver steatosis, and TNF-alpha in a Chinese population with CHC.

show abstract

Impact of NS5A Sequences of Hepatitis C Virus Genotype 1a on Early Viral Kinetics during Treatment with Peginterferon‐α2a plus Ribavirin

Abstract: Genetic variability of HCV-1a NS5A does not predict responsiveness to IFN- alpha . Differences in early kinetics during combination therapy are not due to selection of IFN-resistant HCV strains.

Cited by 16 publications

References 30 publications

Mutations in the E2 and NS5A regions in patients infected with hepatitis C virus genotype 1a and their correlation with response to treatment

Mutations in the E2 and NS5A regions in patients infected with hepatitis C virus genotype 1a and their correlation with response to treatment

The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

Serum Level of Adiponectin Correlated with Gender and Genotype in Patients with Chronic Hepatitis C

Contact Info

Product

Resources

About