Remdesivir for Patients Hospitalized with COVID-19 Severe Pneumonia: A National Cohort Study (Remdeco-19).

BACKGROUND: Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. METHODS: We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. RESULTS: Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points between days 1 and 29. Improvement in the WHO-CPS and the SOFA score were observed in 83.5% and 79.3% of patients, respectively, from day 10. However, there was no effect of remdesivir on the 90-day survival based on the control cohort for hospitalized COVID-19 patients with invasive ventilation. CONCLUSIONS: SOFA score appeared to be an attractive approach to assess remdesivir efficacy and stratify its utilization or not in critically ill patients with COVID-19. This study brings a new clinical benchmark for therapeutic decision making and supports the use of remdesivir for some hospitalized COVID-19 patients.

Observational study on off-label use of tocilizumab in patients with severe COVID-19.

BACKGROUND: In December 2019 a novel coronavirus designated SARS-CoV-2 was identified, and the disease COVID-19 has caused many deaths. SARS-CoV-2 infection has been associated with the development of cytokine storm (including interleukin 6 (IL-6)), which can cause lung damage and lack of oxygen. Tocilizumab (TCZ) inhibits ligand binding to the IL-6 receptor and may be a potential treatment for the hyperinflammation symptoms of COVID-19. However, data regarding the efficacy of TCZ in COVID-19 are lacking. The rapid spread of the pandemic in France, especially in the Paris region, constrained us to the off-label use of TCZ in patients with severe clinical conditions. METHODS: A single-centre observational cohort study of 44 patients infected with COVID-19 was carried out between 6 April and 21 April 2020 in Groupe Hospitalier Intercommunal Le Raincy-Montfermeil (GHILRM). Twenty-two patients diagnosed with COVID-19 were treated with TCZ and were compared with 22 patients not treated with TCZ matched for age, gender and length of hospital stay for COVID-19. Respiratory rate and oxygen supplementation as well as laboratory parameters (such as C-reactive protein (CRP), aspartate aminotransferase and alanine aminotransferase) were collected at baseline and during 14 days of follow-up. Our primary objective was to assess the efficacy of TCZ on respiratory clinical conditions. FINDINGS: The average respiratory rate was lower in the TCZ group than in the control group (21.5 vs 25.5 breaths/min at day 14, 95% CI -7.5 to -0.4; p=0.03). Treated patients tended to be intubated less during the course of the disease (2/22 vs 6/22, 95% CI -0.4 to 0.1; p=0.12). In each group, 10 patients no longer required oxygen therapy. We found a significant decrease in CRP in treated patients on day 7 (p=0.04). TCZ caused cytolysis in more than half (14/22) of the patients but without clinical impact. INTERPRETATION: There was a significant difference in the respiratory rate on day 14 of follow-up, with a greater decrease observed in the treated group. Fewer patients required mechanical ventilation in the TCZ group, especially among patients with more extensive CT lung damage, than in the control group. The same number of patients were weaned off oxygen on day 14 in the two groups, while the patients in the TCZ group had more severe impairment at inclusion. We consider that TCZ showed significant control of the biological inflammatory syndrome, suggesting that it may limit the effect of the cytokine storm. Our study seems to indicate the efficacy of TCZ, particularly in patients with severe initial pulmonary impairment. Selecting the best candidates and the best timing for TCZ therapy needs to be determined in randomised clinical trials.

Conference Scene: Systems biology and personalized health science and translation.

After a 1-day advanced course on systems biology, the main themes of this 3-day colloquium were developed: from systems biology to systems medicine with special applications to cancer; pharmacogenomics in drug discovery and clinical application; and epigenomics and genome-wide association studies in cardiovascular diseases. In two roundtable discussions on pharmacogenomics and genome-wide association studies, the progress and the difficulties in the implementation of omics technologies in clinical practice were discussed. Three workshops were also organized on technical tools linked to the meeting themes.

Availability of pharmacogenetic and pharmacogenomic information in anticancer drug monographs in France: personalized cancer therapy.

AIM: To determine the availability of pharmacogenetic and pharmacogenomic information for healthcare professionals in France during 2009 for anticancer drugs. MATERIALS & METHODS: We searched in the informatic version of the VIDAL dictionary which is currently used by healthcare professionals in France. We then compared this with data available in the PubMed database. RESULTS: Among the 109 anticancer molecules available in France during 2009, 13 have pharmacogenomic or pharmacogenetic information in their monographs. In the scientific literature, we found numerous pharmacogenomic and pharmacogenetic biomarkers concerning 43 of the 109 anticancer agents. Some are pharmacogenomic biomarkers related to drug effectiveness, others are pharmacogenetic biomarkers related to drug toxicity. CONCLUSION: We believe that the lack of pharmacogenomic and pharmacogenetic information in drug monographs reflects the relative newness of the discipline. However, pharmacogenetics and pharmacogenomics can offer valuable information for improving the safety of drugs, reducing toxicity and predicting nonresponders. The drugs might then be incorporated into clinical practice through several strategies, including increased drug labeling and better education of healthcare professionals.

Biological and genetic factors associated with ABCB1 and pregnane-X-receptor expressions in peripheral blood mononuclear cells in the STANISLAS cohort.

BACKGROUND: ABCB1 is a membrane transporter ubiquitously expressed particularly in peripheral blood mononuclear cells (PBMCs). Resistance to drugs is associated with genetic variations of its gene and with modulation of its expression through the pregnane-X-receptor (PXR) transcription factor. We have previously shown that ABCB1 polymorphisms were associated with blood lipid concentrations. METHODS: We wanted to investigate the variation factors and the genetic determinants of ABCB1 and PXR expressions in PBMCs, and their interrelationships with plasma lipid levels. ABCB1 and PXR mRNA were quantified by real-time quantitative RT-PCR in PBMCs of 42 men and 39 women. RESULTS: ABCB1 and PXR were both expressed in PBMCs of all individuals, but their expressions were not significantly correlated. ABCB1 mRNA was correlated with body mass index (BMI; p=0.01) and age (p=0.03). In women, lymphocyte count also correlated with ABCB1 transcripts (p<0.01). After adjustment for BMI, correlation with age disappears. PXR mRNA expression depends on gender with men expressing higher PXR levels (p=0.01). PXR expression also correlates with γ-glutamyltransferase (GGT; p=0.02), but this disappeared after adjustment. CONCLUSIONS: Neither ABCB1 nor PXR expressions correlate with ABCB1 gene variants. Finally, association between ABCB1 or PXR expression in PBMCs and lipid or apolipoprotein plasma concentrations were not significant in this subset of healthy subjects. These results should be confirmed in a larger population sample and extended to patients with various cardiovascular risk profiles.

Association of ABCB1 gene polymorphisms with plasma lipid and apolipoprotein concentrations in the STANISLAS cohort.

BACKGROUND: While involvement of ABCB1 is well known in drug transport, its metabolite transport role is not so well understood. Like other ABC transporters, ABCB1 might be implicated in cholesterol homeostasis and ABCB1 polymorphisms which are responsible for drug resistance might affect lipid homeostasis. Our objective was thus to investigate the implication of ABCB1 polymorphisms and haplotypes in the genetic variability of lipid constituents in healthy people. METHODS: T-129C, G-1A, A61G, G1199A, C1236T, T-76A, G2677T/A and C3435T polymorphisms were genotyped in 371 supposed healthy individuals from the STANISLAS cohort. Each polymorphism was tested with plasma concentrations of total cholesterol, HDL and LDL cholesterol, triglycerides and apolipoproteins A1, B, C3 and E. RESULTS: After adjustment for covariates, carriers of at least one 3435T allele had a significant higher level of apolipoprotein A1 (p = 0.005). In addition, significant correlations were observed in a sex-dependent manner. Women carrying either T-76 or 1236T allele (tendency with G-1 and 2677T/A) had lower total cholesterol (p < or = 0.01) and apolipoprotein B (T-76 exclusively, p=0.002). Haplotypes analysis was not more informative than the single polymorphisms except G2677T/A-C3435T haplotypes for apolipoprotein A1 concentration. CONCLUSION: ABCB1 polymorphisms contribute to the genetic variability of plasma values of lipids and lipoproteins in healthy people.

Determination of ABCB1 polymorphisms and haplotypes frequencies in a French population.

The ATP-binding cassette (ABC) transporter ABCB1, or P-glycoprotein, is a transmembrane efflux pump well known for its implication in drug transport and chemoresistance. ABCB1 substrates include either drugs, such as antiretrovirals and immunomodulators, or physiological molecules like phospholipids. Pharmacogenetic analysis of ABCB1 polymorphisms, in addition to other xenobiotic metabolizing enzymes, might help to personalize and optimize drug therapy. Indeed, some polymorphisms of ABCB1 have been implicated in susceptibility to diseases, changes in drug pharmacokinetics, and in variation of the biological response to drug treatment. In addition, variant and haplotype distributions differ depending on ethnicity. Thus, some ethnies may be at higher risk for adverse events, inefficacy of treatment or prevalence of pathologies. This study aimed to determine frequencies of ABCB1 polymorphisms and haplotypes in a sample of French healthy individuals. DNA was isolated from blood-EDTA. Polymerase chain reaction-restriction fragment length polymorphism and TaqMan single nucleotide polymorphism genotyping assays were used to genotype 227 individuals for T-129C, G-1A, A61G, G1199A, C1236T, T-76A, G2677T/A and C3435T polymorphisms. The observed frequencies of the variant allele for these eight polymorphisms are 0.04, 0.08, 0.09, 0.06, 0.42, 0.46, 0.45 and 0.46 respectively. These polymorphisms are in linkage disequilibrium and haplotype frequencies were determined, the most frequent haplotype being the one with variants at position 1236, 2677 and 3435 and wild-type alleles at the other positions. Finally, the frequencies of these eight ABCB1 polymorphisms in our French individuals supposed to be healthy population are quite similar to those described in other Caucasian populations except for the C3435T polymorphism.

Comparison of two target genes for detection and genotyping of Giardia lamblia in human feces by PCR and PCR-restriction fragment length polymorphism.

A PCR assay targeting the tpi gene was developed to detect and to genotype Giardia lamblia in human feces. Our assay was specific and discriminated between G. lamblia assemblages A and B. G. lamblia cysts isolated from human feces were also analyzed with two previously described PCR-restriction fragment length polymorphism (RFLP) assays, which are based on the detection of tpi or gdh genes. These RFLP analyses distinguished groups I and II within assemblage A or groups III and IV within assemblage B. Among 26 fecal samples from patients with sporadic giardiasis diagnosed by hospital laboratories, the tpi gene was amplified from 25 (96%) with our PCR assay, whereas only 21 (81%) samples were positive when the gdh gene was targeted. Of the 25 positive samples, nine (36%) contained assemblage A and 16 (64%) contained assemblage B. Thus, RFLP analysis classified eight samples (32%) in assemblage A group II, eight (32%) in assemblage B group III, and five (20%) in assemblage B group IV. The group could not be specified for four samples. The tpi and gdh genes of G. lamblia assemblage B were amplified from 14 (93%) of 15 samples collected only from French soldiers coming back from the Ivory Coast. All of these contained assemblage B group III. The PCR method developed is sensitive, simple, and specific and shows that the tpi gene is well adapted for G. lamblia genotyping.