Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates.

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed.

Papillomavirus and cancers: should we extend vaccination to boys in France?

Background: In 2006, the HPV (Human papillomavirus) 6/11/16/18 quadrivalent vaccine was approved by the European Medicines Agency and obtained its marketing authorization in both girls and boys. Currently, the French guidelines recommend and refund vaccination of girls aged 11 to 14 with a catch-up program for females from 15 to 19 years old. Discussion: In France, HPV vaccination coverage tends to decrease. At the end of 2015, the vaccination coverage with three doses reached only 14% in 16-year-old girls (three doses). Although men are also affected by HPV-related diseases such as anal cancer, ano-genital warts, penile cancer or upper aerodigestive tract cancer, vaccine recommendations in France are for girls only. To face the high prevalence of anal cancer and related diseases, the best option is vaccination. Moreover, by offering men a way to prevent diseases against which they do not have any protection yet, universal vaccination could better take into account the ethical issues of prevention. In this paper, we present the point of view of different medical specialties concerning the potential benefit of extending vaccination to boys. Conclusion: HPV vaccination of both genders could benefit from a better public acceptance and contribute to a better coverage, especially in countries with low vaccination rates.

Scoring and psychometric validation of the 'Determinants of Intentions to Vaccinate' (DIVA©) questionnaire.

BACKGROUND: Primary care physicians (PCPs) play a key role regarding vaccination in France. The aims of the present study were to define the scoring rules and to assess the measurement properties of the 'Determinants of Intentions to Vaccinate' (DIVA©) questionnaire that aims to assess PCPs' attitudes and beliefs toward vaccination. METHODS: The DIVA questionnaire was derived from a literature review and PCPs focus groups. Scoring and early validation of the DIVA questionnaire were determined during a cross-sectional study conducted in France. During the study, PCPs had to complete the DIVA questionnaire for any of the six vaccine-preventable diseases (VPDs) to which they were randomly assigned (measles, pertussis, pneumococcus infection, seasonal influenza, human papillomavirus -HPV- infection and tetanus). Descriptive analyses of items and the analysis of the grouping of items into domains were conducted. Internal consistency reliability and construct validity was assessed according to each VPD. RESULTS: The DIVA questionnaire was completed by 1,069 PCPs and was well accepted. The 'Commitment of the PCP to the vaccination approach' score showed very good internal consistency reliability (Cronbach's alpha >0.70 overall and for each VPD). The construct validity of the DIVA questionnaire was confirmed. CONCLUSIONS: The DIVA questionnaire is a valid and reliable measure of PCPs' attitudes and beliefs toward vaccination.

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.

[The commitment of French general practitioners to vaccination: the DIVA study (Determinants of Vaccination Intentions)]. / L’engagement des médecins généralistes français dans la vaccination : l’étude DIVA (Déterminants des Intentions de Vaccination).

OBJECTIVES: Vaccination is an effective way to reduce morbidity and mortality related to infectious diseases. In France, primary care physicians are the main administrators of vaccines. Our objective was to conduct an exploratory qualitative study with primary care physicians to identify determinants of their commitment to vaccination. METHODS: A qualitative research study was conducted with 36 primary care physicians from different geographical regions in France. Six focus group discussions, following a semi-structured interview guide, were held. Qualitative analysis based on coding of the transcribed discussions was performed to identify the factors influencing primary care physicians' attitudes toward vaccination. These factors were then organized into themes. Saturation was also evaluated. RESULTS: Diphtheria, tetanus, poliomyelitis, measles, mumps, rubella, hepatitis B, tuberculosis, pneumococcal infections, meningococcus, human papillomavirus, rotavirus, pertussis, varicella and flu vaccinations were all discussed in each focus group. Saturation was reached from the fourth focus group. Forty identified determinants were divided into six themes: vaccine characteristics, disease characteristics, primary care physicians' past experience, practical aspects, expected benefits and primary care physician-patient relationship. CONCLUSIONS: This study identified the behavioural and organizational determinants influencing primary care physicians' attitudes toward vaccination. These attitudes and determinants varied according to diseases and vaccines. The identified determinants and themes were used as a basis for the development of a questionnaire evaluating the Determinant of Vaccination Intentions (DIVA) of primary care physicians.

The impact of 2-dose routine measles, mumps, rubella, and varicella vaccination in France on the epidemiology of varicella and zoster using a dynamic model with an empirical contact matrix.

PURPOSE: Varicella has a high incidence affecting the vast majority of the population in France and can lead to severe complications. Almost every individual infected by varicella becomes susceptible to herpes zoster later in life due to reactivation of the latent virus. Zoster is characterized by pain that can be long-lasting in some cases and has no satisfactory treatment. Routine varicella vaccination can prevent varicella. The vaccination strategy of replacing both doses of measles, mumps, and rubella (MMR) with a combined MMR and varicella (MMRV) vaccine is a means of reaching high vaccination coverage for varicella immunization. The objective of this analysis was to assess the impact of routine varicella vaccination, with MMRV in place of MMR, on the incidence of varicella and zoster diseases in France and to assess the impact of exogenous boosting of zoster incidence, age shift in varicella cases, and other possible indirect effects. METHODS: A dynamic transmission population-based model was developed using epidemiological data for France to determine the force of infection, as well as an empirically derived contact matrix to reduce assumptions underlying these key drivers of dynamic models. Scenario analyses tested assumptions regarding exogenous boosting, vaccine waning, vaccination coverage, risk of complications, and contact matrices. FINDINGS: The model provides a good estimate of the incidence before varicella vaccination implementation in France. When routine varicella vaccination is introduced with French current coverage levels, varicella incidence is predicted to decrease by 57%, and related complications are expected to decrease by 76% over time. After vaccination, it is observed that exogenous boosting is the main driver of change in zoster incidence. When exogenous boosting is assumed, there is a temporary increase in zoster incidence before it gradually decreases, whereas without exogenous boosting, varicella vaccination leads to a gradual decrease in zoster incidence. Changing vaccine efficacy waning levels and coverage assumptions are still predicted to result in overall benefits with varicella vaccination. IMPLICATIONS: In conclusion, the model predicted that MMRV vaccination can significantly reduce varicella incidence. With suboptimal coverage, a limited age shift of varicella cases is predicted to occur post-vaccination with MMRV. However, it does not result in an increase in the number of complications. GSK study identifier: HO-12-6924.

Cost-effectiveness of routine varicella vaccination using the measles, mumps, rubella and varicella vaccine in France: an economic analysis based on a dynamic transmission model for varicella and herpes zoster.

PURPOSE: Each year in France, varicella and zoster affect large numbers of children and adults, resulting in medical visits, hospitalizations for varicella- and zoster-related complications, and societal costs. Disease prevention by varicella vaccination is feasible, wherein a plausible option involves replacing the combined measles, mumps, and rubella (MMR) vaccine with the combined MMR and varicella (MMRV) vaccine. This study aimed to: (1) assess the cost-effectiveness of adding routine varicella vaccination through MMRV, using different vaccination strategies in France; and (2) address key uncertainties, such as the economic consequences of breakthrough varicella cases, the waning of vaccine-conferred protection, vaccination coverage, and indirect costs. METHODS: Based on the outputs of a dynamic transmission model that used data on epidemiology and costs from France, a cost-effectiveness model was built. A conservative approach was taken regarding the impact of varicella vaccination on zoster incidence by assuming the validity of the hypothesis of an age-specific boosting of immunity against varicella. FINDINGS: The model determined that routine MMRV vaccination is expected to be a cost-effective option, considering a cost-effectiveness threshold of €20,000 per quality-adjusted life-year saved; routine vaccination was cost-saving from the societal perspective. Results were driven by a large decrease in varicella incidence despite a temporary initial increase in the number of zoster cases due to the assumption of exogenous boosting. In the scenario analyses, despite moderate changes in assumptions about incidence and costs, varicella vaccination remained a cost-effective option for France. IMPLICATIONS: Routine vaccination with MMRV was associated with high gains in quality-adjusted life-years, substantial reduction in the occurrences of varicella- and zoster-related complications, and few deaths due to varicella. Routine MMRV vaccination is also expected to provide reductions in costs related to hospitalizations, medication use, and general-practitioner visits, as well as indirect costs, and it is expected to be a cost-effective intervention in France (GSK study identifier: HO-12-6924).

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 1: C2-symmetric inhibitors with diyne and biphenyl linkers.

The discovery of C2-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 2: non-symmetric inhibitors with potent activity against genotype 1a and 1b.

The discovery of non-symmetric thienoimidazole-containing HCV NS5A inhibitors is described. The inhibitors herein reported display high potencies against both genotype 1a and 1b. In this follow-up manuscript, we discuss the importance of the linker aromaticity to achieve high potency, particularly against genotype 1a.

Synthesis and evaluation of NS5A inhibitors containing diverse heteroaromatic cores.

Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.

Benzimidazole-containing HCV NS5A inhibitors: effect of 4-substituted pyrrolidines in balancing genotype 1a and 1b potency.

The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.

A simple semipaced 3-minute chair rise test for routine exercise tolerance testing in COPD.

The functional work capacity of chronic obstructive pulmonary disease (COPD) patients is usually assessed with walk tests such as the 6-minute walk test (6MWT) or the shuttle test. Because these exercise modalities require a controlled environment which limits their use by pulmonologists and severely restricts their use among general practitioners, different modalities of a short (1 minute or less) sit-to-stand test were recently proposed. In this study, we evaluated a new modality of a semipaced 3-minute chair rise test (3CRT) in 40 patients with COPD, and compared the reproducibility of physiological responses and symptoms during the 3CRT and their interchangeability with the 6MWT. The results demonstrate that physiological variables, heart rate, pulse oxygen saturation, work done, and symptoms (Borg dyspnea and fatigue scores), during the 3CRT were highly reproducible, and that the physiological responses and symptoms obtained during the 3CRT and the 6MWT were interchangeable for most patients. Moreover, these preliminary data suggest that patients able to perform more than 50 rises during 3 minutes had no significant disability. The simplicity and ease of execution of the 3CRT will facilitate the assessment of exercise symptoms and disability in COPD patients during routine consultations with pulmonologists and general practitioners, and will thus contribute to the improved management of COPD patients.

Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors.

The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.

[Diagnosis and control of human food poisoning outbreaks]. / Diagnostic et contrôle en médecine humaine des toxi- infections alimentaires collectives.

Medical microbiology laboratories play a key role in the investigation of foodborne disease outbreaks. Bacterial pathogens (Salmonella, Escherichia coli, Campylobacter, Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, etc) have historically been implicated in foodborne illness, while the role of viruses (especially Norovirus) appears to have been underestimated. Culture-based diagnosis has gradually been complemented, or replaced, by rapid molecular methods applied directly to biological samples. These new tools should help to reduce the number of outbreaks in which the etiological agent goes unidentified, and to improve the exhaustiveness of notifications.

Undiagnosed airflow limitation in patients at cardiovascular risk.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) share risk factors and impair each other's prognosis. AIMS: To assess the prevalence of airflow limitation (AL) compatible with COPD in a population at cardiovascular risk and to identify determinants of AL. METHODS: All consecutive patients referred to the cardiovascular prevention unit of a university hospital in 2009 were studied in a cross-sectional analysis. Patients answered questionnaires on socioeconomic status, medical history and lifestyle, and underwent extensive physical examinations, biological measures and spirometry testing. AL was defined as FEV1/FVC<0.70, without any history of asthma. Determinants of AL were assessed using logistic regression. RESULTS: The sample comprised 493 participants (mean age 57.4±11.1 years); 60% were men, 18% were current smokers, 42% were ex-smokers and 10% of patients had a history of CVD. Ten-year risk of coronary heart disease (CHD) according to the Framingham equation was intermediate (10-20%) for 25% of patients and high (>20%) for 10%. Prevalence of AL was 5.9% (95% confidence interval [CI] 4.0-8.3%) in the whole population and 4.3% (2.6-6.6%) among subjects in primary cardiovascular prevention. AL was independently associated with CVD (adjusted odds ratio 4.18, 95% CI 1.72-10.15; P=0.002) but not with Framingham CHD risk. More than 80% of patients screened with AL had not been diagnosed previously and more than one in two patients was asymptomatic. CONCLUSION: Patients with CVD are at increased risk of AL and thus should benefit from AL screening as they are frequently asymptomatic.

Human papillomavirus genotype distribution in oropharynx and oral cavity cancer in France--The EDiTH VI study.

BACKGROUND: The incidence of oropharyngeal cancers has gradually increased over the last decades. Recent studies suggest an association between human papillomavirus (HPV) infection and several head and neck cancers, especially oropharyngeal and oral cavity invasive carcinomas. OBJECTIVES: The objective was to assess the overall and type specific HPV prevalence in oropharyngeal and oral cavity carcinomas in France. STUDY DESIGN: Paraffin-embedded tumour specimens were retrospectively collected in 12 French centres and centrally tested for HPV detection and genotyping (INNO-LiPA assay). RESULTS: A total of 523 cases (77% males) were collected, among which 60% were oropharyngeal and 40% oral cavity carcinomas. The most frequent anatomical sites were tonsil (58.9%) and base of tongue (13.7%) for the oropharynx and floor of mouth (41.1%) and oral tongue (38.3%) for the oral cavity. Overall HPV prevalence was 46.5% in oropharyngeal carcinomas and 10.5% in oral cavity carcinomas and was higher in female than in male cases (63.5% vs 42.2% in oropharynx and 17.2% vs 8.0% in oral cavity). About 95% of HPV-positive cases were infected by a single HPV type. HPV 16 was the most prevalent type and was found in 89.7% and 95.5% of HPV-positive oropharyngeal and oral cavity carcinoma cases, respectively. All other HPV types had prevalence below 5%. CONCLUSIONS: Our results indicate that HPV is common among oropharyngeal and oral cavity carcinoma cases in France and emphasize the predominance of HPV 16. The potential benefit of HPV vaccination on the occurrence of head and neck carcinomas should be further evaluated.