Pattern of HCV antibodies with special reference to NS5A reactivity in HCV-infected patients: relation to viral genotype, cryoglobulinemia and response to interferon

Frangeul, Lionel; Cresta, Pascale; Perrin, M.; Duverlie, Gilles; Khorsi, Hafida; Musset, Lucile; Opolon, P; Huraux, Jean‐Marie; Lunel, F.

doi:10.1016/s0168-8278(98)80275-4

Cited by 22 publications

(20 citation statements)

References 22 publications

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“…It is possible that humoral and cytotoxic responses against these regions drive the changes observed. Indeed, it has been shown that immune responses directed against NS5A correlate with response to IFN therapy (15). Since the V3 region was found to change in responders to a greater extent than in nonresponders, this hypothesis fits with recent data which suggest that strong multispecific immune responses to HCV result in clearance of virus (6).…”

Section: Discussionsupporting

confidence: 80%

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Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy

Nousbaum¹,

Polyak²,

Ray

et al. 2000

J Virol

123

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The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. In this study, the relationship between NS5A mutations and selection pressures before and during antiviral therapy and virologic response to therapy were investigated. Full-length NS5A clones were sequenced from 20 HCV genotype 1-infected patients in a prospective, randomized clinical trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains involved in NS5A functions in vitro were all well conserved before and during treatment. A consensus IFN sensitivity-determining region (ISDR 237-276 ) sequence associated with IFN resistance was not found, although the presence of Ala 245 within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P < 0.01). There were more mutations in the 26 amino acids downstream of the ISDR required for PKR binding in pretreatment isolates from responders versus nonresponders in both HCV-1a-and HCV-1b-infected patients (P < 0.05). In HCV-1a patients, more amino acid changes were observed in isolates from IFN-sensitive patients (P < 0.001), and the mutations appeared to be concentrated in two variable regions in the C terminus of NS5A, that corresponded to the previously described V3 region and a new variable region, 310 to 330. Selection of pretreatment minor V3 quasispecies was observed within the first 2 to 6 weeks of therapy in responders but not nonresponders, whereas the ISDR and PKR binding domains did not change in either patient response group. These data suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of NS5A in HCV replication and antiviral resistance.Hepatitis C virus (HCV) is a major cause of chronic liver disease leading to cirrhosis worldwide and is now recognized as a leading indication for orthotopic liver transplantation in the United States. The HCV genome has a high degree of genetic variability. Interindividual HCV sequence variability has led to the classification of at least six genotypes, while intraindividual variability is referred to as a quasispecies, which usually consists of a predominant viral variant and a variable mixture of highly genetically related yet distinct variants (23, 36).Interferon (IFN) monotherapy leads to sustained virological responses in less than 20% of chronic hepatitis C cases (47). The recent introduction of IFN plus ribavirin combination therapy has significantly improved response rates (8, 38). In multivariate analyses, HCV genotype and high viral load are two important virologic factors that independently predict the likelihood of treatment failure (37, 39)...

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Section: Discussionsupporting

confidence: 80%

“…)ء(‬ In contrast, the major V3 quasispecies variant after 6 weeks of therapy in the two responsive patients was derived from a minor pretreatment V3 quasispecies variant and is highlighted with a pound sign (#). (5,15,22,46,59). In the present study, Ala 245 was more frequently observed in nonresponders than in responders.…”

Section: Discussionsupporting

confidence: 48%

Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy

Nousbaum¹,

Polyak²,

Ray

et al. 2000

J Virol

123

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“…This, however, does not necessarily exclude the latter possibility since we have not yet completely dissected all the antigenic epitopes in NS5A. Our result is consistent with a previous observation that, in a clinical setting with IFN monotherapy, 95% of sustained viral responders, but only 13% of non-responders, had detectable levels of anti-NS5A antibodies in pre-treatment sera (9,10). On the other hand, apparently conflicting observations were reported that detection of anti-NS5A antibodies in pre-treatment sera did not correlate significantly with virological response to IFN treatment (36,44).…”

Section: Discussionsupporting

confidence: 84%

Prediction of Efficient Virological Response to Pegylated Interferon/Ribavirin Combination Therapy by NS5A Sequences of Hepatitis C Virus and Anti‐NS5A Antibodies in Pre‐Treatment Sera

El-Shamy

Sasayama

Nagano-Fujii

et al. 2007

Microbiology and Immunology

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A considerable number of patients infected with Hepatitis C virus subtype 1b (HCV‐1b) do not respond to pegylated interferon/ribavirin combination therapy. In this study we explored a useful factor(s) to predict treatment outcome. A total of 47 HCV‐1b‐infected patients were treated with pegylated interferon/ribavirin for 48 weeks. Sera of the patients were examined for the entire NS5A sequence of the HCV genome, HCV RNA titers and anti‐NS5A antibodies. According to their responses, the patients were divided into two groups, early viral responders who cleared the virus by week 16 (EVR[16w]) and those who did not (Non‐EVR[16w]). The mean number of mutations in the V3 region (aa 2356 to 2379) or that in the V3 region plus its N‐terminally flanking region, which we refer to as interferon/ribavirin resistance‐determining region (IRRDR; aa 2334 to 2379), of NS5A obtained from the pretreatment sera was significantly larger for EVR(16w) compared with Non‐EVR(16w). Moreover, HCV‐1b isolates with ≥5 mutations in V3 or those with ≥6 mutations in IRRDR were almost exclusively found in EVR(16w). Also, the presence of detectable levels of anti‐NS5A antibodies in the pretreatment sera was closely associated with EVR(16w). In conclusion, a high degree of sequence variation in V3 (≥5) or IRRDR (≥6) and the presence of detectable levels of anti‐NS5A antibodies in the pretreatment sera would be useful factors to predict EVR(16w). On the other hand, a less diverse sequence in V3 (≤4) or IRRDR (≤5) together with the absence of detectable anti‐NS5A antibodies could be a predictive factor for Non‐EVR(16w).

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“…As is the case with most biological parameters, the presence of these antibodies in sustained responders and their absence in non-responders is not absolute. Recently, Frangeul et al [1998] reported that only 13% of non-responders and 95% of sustained responders had antibodies to NS5a and concluded that long-term response to IFN was significantly correlated with high NS5a titres. In the first cohort of patients we examined (Group 1) the PPV for non-sustained response for the absence of antibodies to NS4a or anti-NS5a at baseline was 95 and 92%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of anti‐NS4a and anti‐NS5a predict treatment response of patients with chronic hepatitis C

Desombere

Vlierberghe

Weiland

et al. 2007

Journal of Medical Virology

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In order to understand better the clinical significance and prognostic value of antibody responses to HCV proteins and in search for parameters that may allow the early identification of non-sustained responders to therapy, antibody levels were measured against NS3, NS4a and NS5a at baseline in the serum of 120 patients chronically infected with HCV of genotype 1 that were classified as sustained responders, relapsers, or non-responders to therapy. The capacity of these antibody tests to predict therapy-outcome was evaluated. While no differences were observed in the anti-NS3 responses in these different response groups, anti-NS4a and anti-NS5a antibodies were observed more frequently and at higher titres in sustained responders versus non-responders or non-sustained responders (=non-responders + relapsers). Based on this observation, a combination of test results consisting of 'the absence of NS4a (AA 1687-1718) antibody at baseline and the presence of HCV-RNA exceeding 10(5) IU/ml after 1 week of treatment' was identified which predicts non-sustained response to treatment with 100% certainty. Replacing the HCV-RNA decision limit by a HCV-core antigen level of >15 pg/ml resulted in the same predictive value. The proposed algorithm also holds for patients treated with peg-interferon and ribavirin. In conclusion, in patients with chronic HCV infection, the decision to continue or stop treatment can be made after 1 week of treatment with (peg)-interferon alpha and ribavirin.

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Pattern of HCV antibodies with special reference to NS5A reactivity in HCV-infected patients: relation to viral genotype, cryoglobulinemia and response to interferon

Cited by 22 publications

References 22 publications

Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy

Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy

Prediction of Efficient Virological Response to Pegylated Interferon/Ribavirin Combination Therapy by NS5A Sequences of Hepatitis C Virus and Anti‐NS5A Antibodies in Pre‐Treatment Sera

Serum levels of anti‐NS4a and anti‐NS5a predict treatment response of patients with chronic hepatitis C

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