Microvascular Inflammation of Kidney Allografts and Clinical Outcomes.

BACKGROUND: The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. METHODS: We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression. RESULTS: A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation. CONCLUSIONS: Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.).

Evaluation of non-invasive biomarkers of kidney allograft rejection in a prospective multicenter unselected cohort study (EU-TRAIN).

Non-invasive biomarkers are promising tools for improving kidney allograft rejection monitoring, but their clinical adoption requires more evidence in specifically designed studies. To address this unmet need, we designed the EU-TRAIN study, a large prospective multicentric unselected cohort funded by the European Commission. Here, we included consecutive adult patients who received a kidney allograft in nine European transplant centers between November 2018 and June 2020. We prospectively assessed gene expression levels of 19 blood messenger RNAs, four antibodies targeting non-human leukocyte antigen (HLA) endothelial antigens, together with circulating anti-HLA donor-specific antibodies (DSA). The primary outcome was allograft rejection (antibody-mediated, T cell-mediated, or mixed) in the first year post-transplantation. Overall, 412 patients were included, with 812 biopsies paired with a blood sample. CD4 gene expression was significantly associated with rejection, while circulating anti-HLA DSA had a significant association with allograft rejection and a strong association with antibody-mediated rejection. All other tested biomarkers, including AKR1C3, CD3E, CD40, CD8A, CD9, CTLA4, ENTPD1, FOXP3, GZMB, ID3, IL7R, MS4A1, MZB1, POU2AF1, POU2F1, TCL1A, TLR4, and TRIB1, as well as antibodies against angiotensin II type 1 receptor, endothelin 1 type A receptor, C3a and C5a receptors, did not show significant associations with allograft rejection. The blood messenger RNAs and non-HLA antibodies did not show an additional value beyond standard of care monitoring parameters and circulating anti-HLA DSA to predict allograft rejection in the first year post-transplantation. Thus, our results open avenues for specifically designed studies to demonstrate the clinical relevance and implementation of other candidate non-invasive biomarkers in kidney transplantation practice.

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

AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Pharmacovigilance. Withdrawal and rebound effects: not just with psychotropic drugs]. / Pharmacovigilance. Sevrage et effet rebond: pas seulement avec les psychotropes.

The list of drugs whose abrupt discontinuation is likely to induce withdrawal symptoms or a rebound in the pathology being treated is not limited to psychotropic drugs. It includes a number of somatic drugs (e.g. proton pump inhibitors, opioids, triptans, fingolimod, corticosteroids, antiepileptics, nootropics, antiparkinsonians, denosumab, beta-blockers, laxatives, nasal vasoconstrictors, etc.). This type of unintended effect, often underestimated, generally results from a drug-induced homeostatic imbalance that persists after the drug has been discontinued. Taking this risk into account right from the initial prescription should make it possible to prevent such complications, by encouraging intermittent use of the drug, or by applying a very gradual reduction in dosage when a regular treatment is stopped.

La liste des médicaments dont l'arrêt brusque est susceptible d'entraîner des symptômes de sevrage ou un rebond de la pathologie traitée ne se limite pas aux psychotropes, mais inclut un certain nombre de médicaments somatiques (inhibiteurs de la pompe à protons, opioïdes, triptans, fingolimod, corticostéroïdes, antiépileptiques, nootropes, antiparkinsoniens, dénosumab, bêtabloquants, laxatifs, vasoconstricteurs nasaux, etc.). Ce type d'effet indésirable, souvent méconnu, résulte en général d'un déséquilibre homéostatique causé par le médicament, persistant après son interruption. La prise en compte de ce risque dès la prescription initiale devrait permettre de prévenir ces complications, en privilégiant un recours intermittent au médicament ou en prévoyant une diminution très progressive des posologies au moment de mettre un terme à un traitement continu.

Four cases of audio-vestibular disorders related to immunisation with SARS-CoV-2 mRNA vaccines.

OBJECTIVE: To gain medical insight into the clinical course and safety of otolaryngologic disorders following immunisation with severe acute respiratory coronavirus (SARS-CoV-2) mRNA-based vaccines. DESIGN: Case description. STUDY SAMPLE: We report four cases of transient audio-vestibular symptoms, which occurred shortly after inoculation of two BNT162b2 (Pfizer-BioNTech®) and mRNA-1273 (Moderna®) vaccines. RESULTS: Hearing loss was unilateral in all cases and recovered at least partially: it was associated with persistent gait instability in two cases, after 1 and 7 months. Trigger mechanisms underpinning audio-vestibular impairment remain uncertain. Immune tolerance mechanisms with off-target innate activation of T-lymphocytes may be involved in vestibulocochlear nerve disorders, as for other cranial nerves involvement. CONCLUSIONS: The occurrence of audio-vestibular manifestations following mRNA-based vaccines needs ENT monitoring to support their causality in such rare vaccine-related adverse events. Audio-vestibular disorders appeared of transitory nature, including hearing loss, and should not deter further efforts in large-scale vaccination campaigns against SARS-CoV-2.

[Janus kinase inhibitors : new perspectives for precision medicine ?] / Inhibiteurs des Janus kinases : nouvelles perspectives pour la médecine de précision ?

Janus kinase inhibitors (JAKi), such as tofacitinib, baricitinib, upadacitinib or ruxolitinib, are small molecules active on specific intracellular targets and used orally for the treatment of autoimmune or myeloproliferative diseases. Their remarkable therapeutic efficacy is offset by a significant risk of toxicities, essentially dose-dependent and a variable pharmacokinetic profile. The JAKi represent a new therapeutic armamentarium for treating autoimmune, myeloproliferative and inflammatory diseases (incl. COVID-19), but require thorough treatment individualization and close monitoring. Therapeutic Drug Monitoring (TDM) of JAKi could allow a personalized prescription and improve the efficacy-toxicity profile.

Les inhibiteurs des Janus kinases (JAKi), tels que le tofacitinib, le baricitinib, l'upadacitinib ou le ruxolitinib, représentent une nouvelle classe de petites molécules actives sur des cibles intra-cellulaires spécifiques, utilisables par voie orale pour traiter des maladies autoimmunes ou néoplasies myéloprolifératives. Leur efficacité thérapeutique remarquable est contrebalancée par un risque significatif de toxicités essentiellement dose-dépendantes et un profil pharmacocinétique variable. Les JAKi constituent une nouvelle arme thérapeutique pour le traitement des maladies autoimmunes, myéloprolifératives et inflammatoires (Covid-19), mais nécessitent une individualisation et un suivi attentifs. Le suivi thérapeutique des médicaments des JAKi pourrait permettre de personnaliser leur prescription et améliorer leur profil efficacité-toxicité.

Direct-acting antiviral interactions with opioids, alcohol or illicit drugs of abuse in HCV-infected patients.

The hepatitis C virus (HCV) prevalence is extremely high in patients who consume and inject illicit drugs. Concerns about poor adherence and fear of interaction with drugs of abuse could constitute further disincentive for treatment initiation in these patients. We discussed the pharmacokinetics (PKs) and pharmacodynamics (PD) of currently prescribed direct antiviral agents (NSA5 inhibitors: daclatasvir, elbasvir, ledipasvir, pibrentasvir, velpatasvir; NS5B inhibitor: sofosbuvir; NS3/4A protease inhibitors: glecaprevir, grazoprevir, voxilaprevir) and most common substances of abuse (opioids: buprenorphine, fentanyl, heroin, methadone, morphine, oxycodone; stimulants: amphetamines, cathinones, cocaine; cannabinoids; ethanol). Overall, most direct-acting antivirals (DAAs) are substrates and inhibitors of the transmembrane transporter P-glycoprotein (P-gp), and several of them are metabolized by cytochrome P450 enzymes. Clinically relevant interactions are associated with P-gp and CYP3A modulators. Most substances of abuse are eliminated by Phase I and Phase II metabolizing enzymes, but none of them are either major inhibitors or inducers. PK studies did not show any relevant interactions between DAA and methadone or buprenorphine. Based on pharmacological considerations, neither efficacy loss nor adverse drug event associated with detrimental interaction are expected with opioids, stimulants, cannabinoids and ethanol. In summary, our literature review shows that the interaction potential of DAA with most opioids and illicit drugs is limited and should not be a hurdle to the initiate DAA.

[Pharmacogenomics : a toolbox to improve drug prescription]. / Pharmacogénomique et aide à la prescription médicamenteuse.

As a result of advances in pharmacogenomics (PGx), the paradigm that a single dose of a drug is extrapolated to an entire population is set to change. Personalising drug prescriptions according to individual genomic determinants would make it possible to increase the effectiveness and tolerance of treatments. In Switzerland, any doctor can prescribe validated PGx tests for five actionable drugs : abacavir, carbamazepine, thiopurines [azathioprine], fluoropyrimidines [5-FU, capecitabine] and irinotecan. Such an approach presupposes that PGx data are shared with trained clinicians and that prescribing aids can guide them.

Suite aux progrès de la pharmacogénomique (PGx), le paradigme qui veut qu'une dose unique d'un médicament soit extrapolée à l'ensemble d'une population est appelé à évoluer. Une personnalisation de la prescription médicamenteuse en fonction de déterminants génomiques individuels permettrait d'augmenter l'efficacité et la tolérance aux traitements. En Suisse, tout médecin peut réaliser des tests PGx validés pour cinq médicaments actionnables qui sont : l'abacavir, la carbamazépine, les thiopurines (azathioprine), les fluoropyrimidines (5-fluoro-uracile, capécitabine) et l'irinotécan. Une telle approche présuppose que les données PGx soient partagées avec des cliniciens formés et que des outils d'aide à la prescription puissent les orienter.

Modelling the Impact and Cost-effectiveness of Extended Hepatitis C Virus Screening and Treatment with Direct-acting Antivirals in a Swiss Custodial Setting.

BACKGROUND: Hepatitis C virus (HCV) among people living in detention (PLD) is typically high in many countries including Switzerland, where it is estimated that the HCV prevalence rate is between 5.7% and 6.2%. In Switzerland, the existing screening strategy involves routine screening of PLD who indicate they are from HCV high-risk populations based on questionnaire responses upon entry to the detention center, rather than an offer to screen all PLD. METHODS: A cost-effectiveness analysis from a Swiss healthcare provider perspective was conducted by combining a 5-year decision tree screening model with results from a Markov model of HCV treatment outcomes. This model explored the cost-effectiveness of increased HCV screening to cover all PLD compared to the current approach, using a standard test package and subsequent treatment with a single-tablet regimen in Swiss custodial settings. Sensitivity and scenario analyses examined the uncertainty of results. RESULTS: At the willingness-to-pay threshold of 100 000 Swiss Francs (CHF) per quality-adjusted life-year (QALY), comprehensive general screening was cost-effective compared to current risk-based screening, with a base case incremental cost-effectiveness ratio of CHF 14 312 per QALY. The net monetary benefit of screening the whole PLD population was CHF 23 298 046 and CHF 4298 per person. The proportion of PLD tested was predicted to increase from 13.6% to 67.0% under comprehensive screening. CONCLUSION: The results showed that comprehensive screening strategies in detention centers in Switzerland can be cost-effective, with the probabilistic sensitivity analysis estimating an 82.3% probability of cost-effectiveness.

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine.

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

Increasing hepatitis C virus screening in people who inject drugs in Switzerland using rapid antibody saliva and dried blood spot testing: A cost-effectiveness analysis.

People who inject drugs (PWID) are a key high-risk group for Hepatitis C Virus (HCV) infection due to the sharing of needles and drug-preparation equipment. However, only approximately 50% of PWID are currently screened for HCV in Switzerland. At present, screening of PWID occurs in general practice via venepuncture. Compared to venepuncture, screening via rapid antibody saliva and dried blood spot (DBS) tests is well adapted to PWID, who typically have difficult venous access. The cost-effectiveness of an increased access screening programme of PWID (increased screening using rapid antibody saliva tests and DBS tests [semi-quantitative viraemia and viral genotype]) was analysed through a decision tree screening model combined with the outputs of a Markov treatment model. Sensitivity and scenario analyses examined the uncertainty of results. At a willingness to pay (WTP) threshold of CHF 100 000 (USD 105 000) per quality-adjusted life year (QALY), the increased access screening programme was cost-effective compared to current screening, with a base case incremental cost-effectiveness ratio of CHF 7 940 (USD 8337) per QALY. The net monetary benefit was CHF 959 802 668 (USD 1 007 792 801) for the PWID population and CHF 94 469 (USD 99 192) per person. The increased access screening programme had a 97.0% probability of being cost-effective compared to the current screening method at the WTP threshold of CHF 100 000 (USD 105 000). The results showed an increased access screening programme that uses tests which are better suited to the PWID population to be more cost-effective, due to the increased uptake that rapid antibody saliva and DBS tests generate.

Blood-borne and sexually transmitted infections: a cross-sectional study in a Swiss prison.

BACKGROUND: Incarcerated people carry a high burden of infection, including blood-borne diseases (BBDs). It is also known that one million people contract a sexually transmitted infection (STI) every day worldwide, which represents a global public health challenge. However, data regarding the prevalence of STIs and the risk factors among incarcerated populations are lacking. The objective of this study was to determine the prevalence and associated factors of BBDs and STIs among detainees in the largest pre-trial prison in Switzerland. METHODS: In a cross-sectional study conducted at the Champ-Dollon pre-trial prison, 273 male detainees answered a standardized questionnaire and were screened for syphilis, herpes simplex virus 2 (HSV-2), HIV, and hepatitis C (HCV). Prevalence rates and associations of BBDs and STIs with risk factors were computed. RESULTS: Most participants (90.9%) were migrants from outside Western Europe, and 5.9% were injecting drug users. HCV was diagnosed among 6.2% of participants (antibody prevalence). The prevalence of HCV was higher among injecting drug users (81.2%) than non-injectors (1.6%). The prevalence of HIV, syphilis, and HSV-2 was 0.4%, 1.1%, and 22.4%, respectively. HCV was associated with a history of injecting drug use and HSV-2 with a lower education level and being older than 26 years. CONCLUSIONS: This study showed the infection prevalence of 2-9 times higher among detainees than in the Swiss community. It also illustrated that these infections are associated with sociodemographic and risk factors. Therefore, the prison environment offers an opportunity to strengthen infectious disease control programs targeting specific subgroups of at-risk people. Such programs would benefit both the prison population and broader society.

Drug- and Toxin-Induced Opsoclonus - a Systematized Review, including a Case Report on Amantadine-Induced Opsoclonus in Multiple System Atrophy.

Background: Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus. Methods: Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies. Results: The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus. Conclusion: Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology.

Prevalence of actionable pharmacogenetic variants and high-risk drug prescriptions: A Swiss hospital-based cohort study.

Drug type and dosing recommendation have been designed and optimized based on average response in the general population. Yet, there is significant inter-individual variability in drug response, which results in treatment inefficacy or adverse drug reactions in a subset of patients. This is partly due to genetic factors that typically affect drug metabolism or clearance. To verify the relevance and applicability of international pharmacogenetic guidelines in the Swiss population, we genotyped 1533 patients from a hospital-based biobank who received at least 30 different drugs, as documented in their electronic health record. We then assessed the prevalence of clinically actionable variants in 13 high-risk pharmacogenes. We compared the allele frequencies obtained in the hospital-based cohort with those of a Swiss population-based cohort of 4791 individuals. The prevalence of clinically actionable variants was comparable between the two cohorts, with most study participants (97.3%) carrying at least one actionable pharmacogenetic variant. We then assessed the frequency of high-risk prescriptions due to actionable gene-drug interactions and observed that 31% of patients in the hospital-based cohort were prescribed at least one drug for which they carried a high-risk variant, and for which international guidelines recommend a change of drug or dosage. Our analysis confirms the high prevalence of actionable pharmacogenetic variants in the Swiss population. It also shows that a substantial minority of patients are exposed to drugs for which they carry potentially problematic variants. Implementing a genetically informed approach to drug prescribing could have a positive impact on the quality of healthcare delivery.

Guidance for the Interpretation of Long-Acting Cabotegravir and Rilpivirine Concentrations Based on Real-World Therapeutic Drug Monitoring Data and Documented Failures.

The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on real-world therapeutic drug monitoring data and documented virologic failures, this article provides a reappraisal of the existing thresholds and guidance for the interpretation of cabotegravir and rilpivirine concentrations.

Exposures to non-therapeutic chemicals before, during and after pregnancy: data from the Swiss Teratogen Information Service (STIS).

AIMS OF THE STUDY: Limited knowledge exists regarding exposures to non-therapeutic chemicals by women planning to conceive, or during pregnancy or breastfeeding. The Swiss Teratogen Information Service (STIS) provides information to healthcare professionals about medications and other exposures during pregnancy or breastfeeding. This study aimed to describe the queries on non-therapeutic chemicals addressed to the STIS over the past two decades. METHODS: Using data from the STIS for the years 2000 to 2019, we conducted a descriptive analysis of all queries related to women's exposures to non-therapeutic chemicals during pregnancy planning, pregnancy or breastfeeding. RESULTS: Over two decades, the STIS database recorded 320 exposures to chemicals. Workplace settings accounted for over 60% of queries, followed by exposures at home (20%). In almost half (48%) of the queries, more than one chemical was mentioned, totalling 885 chemicals across these 320 queries. Commonly mentioned chemicals included isopropanol, acetone and lead. Solvents were the leading category of products (16%), followed by cleaning products (10%), paints (8%) and insecticides (5%). The follow-up data showed five diverse cases of congenital malformations, accounting for 4.0% (5 out of 125) of the sample, a figure in line with the background risk of malformations in the general population. CONCLUSIONS: This study emphasises the importance of conducting research that comprehensively captures the highly heterogeneous exposures to non-therapeutic chemicals during pregnancy and suggests that attention should be given not only to professional settings, but also to domestic contexts.

Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. DESIGN: This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. SETTING: Data were collected from the databases of six Teratology Information Services. PARTICIPANTS: This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. RESULTS: Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. CONCLUSIONS: This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV.

Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.

Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland.

Background: The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported. Methods: SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023. Findings: Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p < 0·01) lower cabotegravir trough in males compared to females. Overall, 172 PWH (92%) remained suppressed and three experienced virologic failures (1·6%), of those, two had sub-optimal drug exposure. No association was found between low trough levels and detectable viral load. Interpretation: Real-world cabotegravir concentrations are substantially lower than previously reported. However, these concentrations appear sufficient to ensure sustained virological suppression in almost every PWH. These reassuring data challenge the rather conservative thresholds adopted to date, which may raise unnecessary concerns. Yet, our study reveals that some PWH have repeatedly very low drug levels, for reasons that remain to be elucidated. Funding: This work was funded by the Swiss National Science Foundation, grant number N◦ 324730_192449. This study received no support from pharmaceutical industries. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The SHCS data were gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers).