Pharmacogenomic-guided clozapine administration based on HLA-DQB1, HLA-B and SLCO1B3-SLCO1B7 variants: an effectiveness and cost-effectiveness analysis.

The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration

Multifocal lymphadenopathies with polyclonal reactions primed after EBV infection in a mRNA-1273 vaccine recipient.

We report a case of recurrent tender, multifocal lymphadenopathies associated with B-symptoms, clinically mimicking lymphoma in a mRNA-1273 vaccine recipient after a recent Epstein-Barr virus (EBV) infection. In the lymph node biopsy, monocytoid B-cell hyperplasia, TH2 (GATA3+) predominance, and hyperplasia of interferon-gamma-producing plasmacytoid dendritic cells were observed along with sustained neutralising antibody production against SARS-CoV-2 wild-type and five variants. High titres of anti-S antibodies and neutralising antibodies were observed, excepted for variant B.1.529** (omicron) and B.1.351** (beta), due to several mutations in the spike protein, including the E484K mutation. We postulated that EBV acted as an immunological enhancer with the mRNA-1273 vaccine, inducing a sustained inflammatory response over several weeks. However, the polyclonal nature of the lymphadenopathy with polytypic plasmacytosis and pseudo-tumoural reaction cell hyperplasia were associated with failure to mount acute phase responses

Health utility indexes in patients with acute coronary syndromes.

BACKGROUND: Acute coronary syndromes (ACS) have been associated with lower health utilities (HUs) compared with the general population. Given the prognostic improvements after ACS with the implementation of coronary angiography (eg, percutaneous coronary intervention (PCI)), contemporary HU values derived from patient-reported outcomes are needed. METHODS: We analysed data of 1882 patients with ACS 1 year after coronary angiography in a Swiss prospective cohort. We used the EuroQol five-dimensional questionnaire (EQ-5D) and visual analogue scale (VAS) to derive HU indexes. We estimated the effects of clinical factors on HU using a linear regression model and compared the observed HU with the average values of individuals of the same sex and age in the general population. RESULTS: Mean EQ-5D HU 1-year after coronary angiography for ACS was 0.82 (±0.16) and mean VAS was 0.77 (±0.18); 40.9% of participants exhibited the highest utility values. Compared with population controls, the mean EQ-5D HU was similar (expected mean 0.82, p=0.58) in patients with ACS, but the mean VAS was slightly lower (expected mean 0.79, p<0.001). Patients with ACS who are younger than 60 years had lower HU than the general population (<0.001). In patients with ACS, significant differences were found according to the gender, education and employment status, diabetes, obesity, heart failure, recurrent ischaemic or incident bleeding event and participation in cardiac rehabilitation (p<0.01). CONCLUSIONS: At 1 year, patients with ACS with coronary angiography had HU indexes similar to a control population. Subgroup analyses based on patients' characteristics and further disease-specific instruments could provide better sensitivity for detecting smaller variations in health-related quality of life

Utilité de la mesure en continu de la glycémie chez les patients diabétiques de type 2 [Value of continuous glucose monitoring in type 2 diabetic patients]

Management of type 1 and type 2 diabetes mellitus is getting complex with the apparition of new treatments, but also new technologies. Among these, continuous glucose monitoring systems (CGMS) lead to a better glycemic control and less hypoglycemia in type 1 diabetic patients. Studies are scarce in type 2 diabetes but also seem to show a benefit, particularly in patients using insulin. Nevertheless, type 2 diabetic patients taking advantage of CGMS must be better defined. In any case, a multidisciplinary approach to the use of CGMS and interpretation of data is warranted

Population pharmacokinetic analysis of doravirine in real-world people with HIV.

The pharmacokinetics of doravirine has been studied in clinical trials but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics in real-world people with HIV (PWH). A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3-6 months). Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared with a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected nonadherence or pregnancy