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Jean-Michel Pawlotsky

Publications and source records attributed to Jean-Michel Pawlotsky.

At least 19 recordsLinked to original sources
PubMed2026

Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Nirsevimab, a long-acting monoclonal antibody targeting a conserved epitope on the prefusion F protein (site Φ), has shown high efficacy in clinical trials and early real-world studies. Although widespread resistance has not been reported, concerns remain about the emergence of escape variants, particularly among RSV-B viruses. During the 2024-25 RSV season in France, RSV-B predominated, providing a unique opportunity to examine breakthrough infections with RSV-B and resistance at a large scale. The study aimed to characterise RSV escape from nirsevimab using genotypic and phenotypic methods. METHODS: This POLYRES-2 project was a multicentre, national, observational study conducted in hospital settings (inpatients and outpatients) across France during the 2024-25 RSV season. We included infants aged 1 year or under with a RT-PCR-confirmed RSV infection in routine care, regardless of whether they had received nirsevimab. Infants were identified through hospital virology laboratory databases. Each participating centre was requested to include a balanced number of nirsevimab-exposed and non-exposed infected infants throughout the study period. Clinical data were retrieved from electronic medical records. We compared RSV susceptibility to nirsevimab in infants who received nirsevimab with that in nirsevimab-naive infants. Respiratory samples were sequenced for full-length RSV genomes. To ensure reliability, phylogenetic and mutational analyses were restricted to high-quality sequences with greater than or equal to 90% genome coverage and complete reads across the nirsevimab-binding site. Clinical RSV isolates were tested for neutralisation by nirsevimab. We analysed F candidate substitutions using a fusion inhibition assay. The primary outcomes were presence of resistance-associated substitutions (RASs) in the RSV F protein (site Φ) and phenotypic resistance to nirsevimab. FINDINGS: Among 1023 RSV-infected infants, 858 (83·9%) had full-length RSV genome sequences: 419 (48·8%) from nirsevimab-treated breakthrough infections (212 [50·6%] RSV-A, 207 [49·4%] RSV-B) and 439 (51·2%) from nirsevimab-naive infants (192 [43·7%] RSV-A, 247 [56·3%] RSV-B). RASs were identified in two of 195 RSV-A breakthrough infections (1·0%) and in 23 of 184 RSV-B breakthrough infections (12·5%). In RSV-A, the only RAS was F:K209E, conferring intermediate resistance. In RSV-B, resistance was more frequent and diverse than in RSV-A: 12 of 23 (52.2%) resistant viruses carried a substitution at residue 208 (F:N208D, F:N208I, F:N208K, F:N208S, or F:N208Y). Additional novel substitutions, including F:I64V/F:K65E, F:K68I, F:L204S, and F:P205S, also mediated resistance. Notably, a resistant RSV-B variant (F:N208S) was detected almost 1 year after prophylaxis. No resistant RSV was detected in nirsevimab-naive infants. INTERPRETATION: Resistance to nirsevimab in RSV-B can emerge in real-world settings, affecting around 12% of breakthrough infections and showing greater diversity than previously recognised, although the clinical impact remains constrained by available evidence. Detection of resistant variants long after prophylaxis highlights the need for extended genomic surveillance. Integration of clinical and virological data will be essential to sustain the long-term effectiveness of RSV monoclonal antibody programmes. FUNDING: This study was supported by a grant from the Agence Nationale de Recherche sur le Sida et les hépatites virales - Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention.

Humans↗
PubMed2006

The nonstructural 5A protein of hepatitis C virus genotype 1b does not contain an interferon sensitivity-determining region.

BACKGROUND: The nonstructural (NS) 5A protein of hepatitis C virus (HCV) has been suggested to contain an interferon (IFN) sensitivity-determining region (ISDR). METHODS: We studied whether the degree of viral decline on day 1 is associated with differences in NS5A amino acid sequences among patients receiving IFN- alpha. RESULTS: Phylogenetic analyses of the full-length protein and of functional domains showed no relationship between the baseline protein sequence and the antiviral response. NS5A quasispecies sequences showed no differences in the number of mutations in the putative ISDR relative to a prototype sequence between responders and nonresponders or according to IFN- alpha antiviral efficacy. No relationship was found between antiviral efficacy at 24 h and the baseline sequence of any NS5A region. Amino acid changes were observed in a few cases at 24 h in both responders and nonresponders, but no consistent pattern of amino acid shifts was observed, ruling out the possibility that IFN- alpha selected IFN-resistant variants. CONCLUSION: Our findings show that there is no ISDR in the HCV genotype 1 NS5A protein and that the NS5A sequence does not influence the capacity of IFN- alpha to block viral replication. The findings do not rule out a role for NS5A in subsequent viral clearance.

Adult↗
PubMed2006

euHCVdb: the European hepatitis C virus database.

The hepatitis C virus (HCV) genome shows remarkable sequence variability, leading to the classification of at least six major genotypes, numerous subtypes and a myriad of quasispecies within a given host. A database allowing researchers to investigate the genetic and structural variability of all available HCV sequences is an essential tool for studies on the molecular virology and pathogenesis of hepatitis C as well as drug design and vaccine development. We describe here the European Hepatitis C Virus Database (euHCVdb, http://euhcvdb.ibcp.fr), a collection of computer-annotated sequences based on reference genomes. The annotations include genome mapping of sequences, use of recommended nomenclature, subtyping as well as three-dimensional (3D) molecular models of proteins. A WWW interface has been developed to facilitate database searches and the export of data for sequence and structure analyses. As part of an international collaborative effort with the US and Japanese databases, the European HCV Database (euHCVdb) is mainly dedicated to HCV protein sequences, 3D structures and functional analyses.

Databases, Protein↗
PubMed2006

Serological viral testing of cadaveric cornea donors.

BACKGROUND: Cornea graft recipients are exposed to viral transmission from the donor. Cadaveric donor serum is often of poor quality and frequently yields falsely positive results in serological assays that may result in the graft being needlessly discarded. OBJECTIVE: We examined the influence of the time of blood collection after death, and the macroscopic aspect of serum, on serological test results in cadaveric cornea donors. METHODS: Five hundred sixty-five consecutive cadaveric cornea donors were systematically tested for serological markers of human immunodeficiency virus type 1 and 2, human T-cell leukemia virus type 1, hepatitis B and hepatitis C viruses (HCV). We studied the influence of the macroscopic aspect of the donor's serum and the time of blood collection after death on the results of serological testing and on the subsequent decision to use or discard the graft. RESULTS: Twenty-one and a half percent of corneas were rejected on the basis of virological test results. We found significant relationships between the macroscopic aspect of serum at the time of testing and: (i) a positive, equivocal or discrepant result of immunoassays, for all markers except anti-HCV antibodies, (ii) non acceptance of cornea grafts, and (iii) the time of blood sampling after death. CONCLUSIONS: The macroscopic aspect of postmortem blood samples is the best predictor of the specificity of serological testing in cornea donors. Serological results should be interpreted with care when serum is macroscopically abnormal, and cadaveric donors should not be sampled more than 12 hr after death.

Cadaver↗
PubMed2006

Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection.

BACKGROUND: We investigated associations between interferon (IFN)-gamma-inducible protein (IP)-10 and liver histological results, viral kinetic response, and treatment outcome in patients infected with hepatitis C virus (HCV) genotypes 1-4. METHODS: Plasma IP-10 was monitored before, during, and after treatment with pegylated IFN- alpha 2a and ribavirin in 265 HCV-infected patients. RESULTS: In univariate analyses, a low baseline IP-10 level was significantly associated with low baseline viral load, rapid viral response (RVR), a sustained viral response (SVR), body mass index <25 kg/m2, and less-pronounced fibrosis, inflammation, and steatosis (for HCV genotypes other than 3). When the results of the univariate analyses were included in multivariate analyses, a low plasma IP-10 level, low baseline viral load, and genotype 2 or 3 infection were independent predictors of an RVR and SVR. IP-10 levels decreased 6 weeks into treatment and remained low in patients with an SVR. By contrast, plasma levels of IP-10 rebounded in patients who had detectable HCV RNA after the completion of treatment. Using cutoff IP-10 levels of 150 and 600 pg/mL for predicting an SVR in patients infected with HCV genotype 1 yielded a specificity and sensitivity of 81% and 95%, respectively. CONCLUSION: Baseline IP-10 levels are predictive of the response to HCV treatment.

Adult↗
PubMed2006

Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin.

BACKGROUND & AIMS: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. METHODS: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 microg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. RESULTS: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. CONCLUSIONS: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1-infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success.

Adult↗
PubMed2006

Hepatitis C virus serologic and virologic tests and clinical diagnosis of HCV-related liver disease.

The use of serological and virological tests has become essential in the management of hepatitis C virus (HCV) infection in order to diagnose infection, guide treatment decisions and assess the virological response to antiviral therapy. Virological tools include serological assays for anti-HCV antibody detection and serological determination of the HCV genotype, and molecular assays that detect and quantify HCV RNA and determine the HCV genotype. Anti-HCV antibody testing and HCV RNA testing are used to diagnose acute and chronic hepatitis C. Only patients with detectable HCV RNA should be considered for pegylated interferon alfa and ribavirin therapy and the HCV genotype should be systematically determined before treatment, as it determines the indication, the duration of treatment, the dose of ribavirin and the virological monitoring procedure. HCV RNA monitoring during therapy is used to tailor treatment duration in HCV genotype 1 infection, and molecular assays are used to assess the end-of-treatment and, most importantly the sustained virological response, i.e. the endpoint of therapy.

Journal Article↗
PubMed2006

Therapy of hepatitis C: from empiricism to eradication.

The complications of chronic hepatitis C virus infection can be prevented by antiviral therapy. The initial choice of interferon alfa and, subsequently, ribavirin as potential treatments for chronic hepatitis C was empirical. Nevertheless, the combination of pegylated interferon alfa and ribavirin has become the standard treatment of chronic hepatitis C. Since the advent of interferon-based therapy, enormous progress has been made in understanding the mechanisms of treatment efficacy and failure, and in everyday patient management. The principal advances are: a better understanding of hepatitis C virus steady-state kinetics and the antiviral mechanisms of interferon and ribavirin; easier treatment decisions thanks to novel assays to assess liver disease severity and the virological characteristics of infection; a better use of virological tests to tailor therapy; a better management of adverse effects; a better understanding of virological treatment failure; and a better management of "special" populations, including patients with decompensated cirrhosis and end-stage liver disease, liver transplant recipients, hemodialysis patients and renal transplant recipients, human immunodeficiency virus-coinfected patients, intravenous drug users and patients on opiate replacement therapy, or virological non responders to previous therapies. Steady-state HCV kinetics offers several potential targets for new drugs. These targets should ideally be hit simultaneously in order to achieve viral eradication within a reasonable time frame. Future drugs for HCV infection will belong to four main categories, including new interferons, alternatives to ribavirin, specific HCV inhibitors, and immune modulators. New treatments and vaccines might make it possible to eradicate HCV in the future.

Antiviral Agents↗
PubMed2006

IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection.

Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP-10 levels prior to treatment with pegylated interferon-alpha-2a and ribavirin. Significantly lower IP-10 levels were observed in patients achieving a rapid viral response (RVR) (P < .0001), even in those with body mass index (BMI) > or = 25 kg/m2 (P = .004) and with baseline viral load > or = 2 million IU/mL (P = .001). Similarly, significantly lower IP-10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P < .05), higher viral load (P = .0005), and both higher BMI and viral load (P < .03). In multivariate logistic regression analyses, a low IP-10 value was independently predictive of both RVR and SVR. A baseline cutoff IP-10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1-infected patients, which was comparable with that observed using a reduction in HCV-RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut-off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP-10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP-10 level is low. Thus, pretreatment IP-10 analysis may prove helpful in decision-making regarding pharmaceutical intervention.

Adult↗
PubMed2006

Molecular epidemiology of hepatitis C virus subtype 3a in injecting drug users.

Hepatitis C virus subtype 3a (HCV-3a) originates from Asia and has spread widely among injecting drug users as well as other patient groups in industrialized countries. HCV subtype 3a infection remains highly prevalent and frequently transmitted in the population of intravenous drug users. The objective of this study was to understand better the mechanisms of the worldwide HCV-3a epidemics in drug users. Ninety-three sera from HCV-3a-infected IDUs from France, the United States, Brazil, Argentina, and Australia were studied. Phylogenetic analyses of the non-structural 5B region showed no specific clustering according to the continent of the patient's origin. Non-exclusive clusters of viral sequences from South America, Australia, and California were observed, but topologies were not supported by strong bootstrap values. The results suggest that HCV-3a has been transmitted from a common origin through a unique worldwide epidemic that rapidly spread among drug users. Regional transmission occurred in the recent past, leading to an embryonic genetic diversification of HCV-3a among local injecting drug user population.

Argentina↗
PubMed2006

Expertise of laboratories in viral load quantification, genotyping, and precore mutant determination for hepatitis B virus in a multicenter study.

A national evaluation study was performed in 14 specialized laboratories with the objective of assessing their capacities to provide (i) hepatitis B virus (HBV) viral loads (VL), (ii) HBV genotypes, and(iii) identification of precore/core mutants. The panel consisted of 12 HBV DNA-positive samples with VLs from 2.8 to 9.1 log(10) copies/ml, different HBV genotypes (A to F), and 3 mutant and 9 wild-type samples at nucleotide 1896. The coefficients of variation of the mean VLs ranged from 2.4% to 10.4% with the Cobas HBV Monitor assay, from 1.8% to 5.5% with the Cobas TaqMan 48, from 1.5 to 26.2% with RealArt HBV PCR, and from 0 to 7% with branched DNA (bDNA). The Cobas Monitor assay underestimated the VLs of genotype F samples, with differences ranging from 1.4 to 2.4 log(10) copies/ml. The accuracies of genotype determinations ranged from 33% to 100%, and those of precore mutant determinations ranged from 25 to 100%. This study showed some drawbacks of two widely used assays: (i) Cobas Monitor has a narrow dynamic range and underestimates genotype F sample VLs and (ii) bDNA shows poor sensitivity and may fail to identify patients with low VLs. With higher performance in terms of analytical sensitivity combined with a larger dynamic range and an ability to quantify the main genotypes equally, real-time PCR methods appear more appropriate for accurate monitoring of HBV DNA quantification. Furthermore, the clinical implications of HBV genotyping and the determination of precore/core mutants need to be clearly stated to justify the standardization of these methods.

France↗
PubMed2006

Unique NS5b hepatitis C virus gene sequence consensus database is essential for standardization of genotype determinations in multicenter epidemiological studies.

A multicenter study of NS5b hepatitis C virus (HCV) genotype determination involving 12 laboratories demonstrates that any laboratory with expertise in sequencing techniques would be able to provide a reliable HCV genotype for clinical and epidemiological purposes as long as they are provided a consensus reference sequence database.

Consensus Sequence↗
PubMed2006

Dynamics of hepatitis B virus resistance to lamivudine.

Lamivudine was the first approved inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT). Lamivudine resistance develops in 53% to 76% of patients after 3 years of treatment. We extensively characterized the dynamics of HBV quasispecies variant populations in four HBV-infected patients who developed lamivudine resistance. Virological breakthrough was preceded by 2 to 4 months by the emergence of quasispecies variants bearing amino acid substitutions at RT position 204, i.e., within the YMDD catalytic motif (rtM204V/I). Three patients had a gradual switch from a YMDD variant population at baseline to a 100% lamivudine-resistant variant population, whereas the remaining patient had a fluctuating pattern of resistance variant dynamics. Careful analysis of amino acid substitutions located outside domain C of HBV RT, including those known to partially restore replication capacities in vitro, showed that the in vivo replication of HBV variants is driven by multiple forces, including intrinsic replicative advantages conferred by mutations accumulating outside domain C and the changing environment in which these variants replicate. Our findings also suggest that individual treatment optimization will require sensitive methods capable of detecting the emergence of viral resistance before the relevant variants acquire optimal replicative capacities.

Adult↗
PubMed2006

Future therapies for hepatitis C.

Although pegylated interferon-alpha plus ribavirin has become the standard for treating chronic hepatitis C virus infection, a substantial number of patients do not tolerate therapy and require dose reduction or discontinuation, or do not respond to this combination therapy. Thus, new therapeutic options are needed. An increased knowledge of the hepatitis C virus and an understanding of its replication cycle, as well as advances in biotechnology, have stimulated the development of numerous new antiviral treatments for patients with hepatitis C virus infection. This review focuses on four classes of new agents: new interferons, ribavirin-like molecules, specific small-molecule hepatitis C virus inhibitors and new immune therapies, with particular emphasis on medications in the later stages of development.

Antiviral Agents↗