Search

Background: The pharmacokinetics of long-acting rilpivirine has mostly been studied in clinical trials, which do not fully address the uncertainties that arise in routine clinical situations., Aims and Methods: Our population analysis aims to establish percentile curves for rilpivirine concentrations in people with HIV (PWH) followed-up in a routine clinical setting, while identifying patient-related factors that may influence rilpivirine exposure. A total of 238 PWH enrolled in our nationwide multicenter observational study contributed to 1038 concentrations (186 and 852 concentrations after oral and intramuscular injection, respectively)., Results: Rilpivirine pharmacokinetics were best described by a two-compartment model with an oral to intramuscular relative bioavailability factor. A simple zero-order absorption process was retained for oral administration while a parallel first-order absorption was used for intramuscular administration, with 27.6% of the dose released via a fast absorption pathway and the remaining fraction via a slow absorption pathway. Our model estimated that long-acting rilpivirine reaches steady-state after 2.5 years and has an elimination half-life of 18 weeks, consistent with published estimates. In females, a 45.6% reduction in the proportion of the dose absorbed via the rapid absorption pathway was observed. However, this resulted in no more than 15% difference in trough concentrations (C trough ) compared to males, which was not considered to be clinically relevant., Conclusion: Overall, our model-based simulations showed that only approximately 50% of long-acting rilpivirine C trough would be above the 50 ng/mL threshold associated with optimal therapeutic response, while approximately 85% of C trough would be above the first quartile of concentrations observed in Phase III trials (32 ng/mL)., Competing Interests: MC reports grants and payment for expert testimony from Gilead, MSD, and ViiV and support for attending meetings from Gilead, paid to his institution. DB reports honoraria for advisory boards, lectures, and travel grants from the companies Gilead, ViiV, and MSD. HG has received unrestricted research grants from Gilead Sciences and ViiV Healthcare; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, GSK, Johnson and Johnson, Janssen, Novartis, and ViiV Healthcare; and grants from the Yvonne Jacob Foundation, from the National Institutes of Health, and unrestricted research grants from Gilead Sciences. The institution of JD received grants from Gilead Sciences and ViiV. BS reports support for travel grants and advisory boards from Gilead Sciences and ViiV, paid to his institution. The institution of HF received educational grants from ViiV, MSD, AbbVie, Gilead, and Sandoz. MS reports advisory board payments to his institution by Gilead, MSD, ViiV, Moderna, and Pfizer. The institution of AR received grants from Gilead, support for attending meetings from Gilead and Pfizer, and advisory board fees from MSD and Moderna. CM has received speaker honoraria from ViiV, MSD, and Gilead. CD received travel grants for congress participation from Gilead. The institution of EB received grants from the Swiss National Science Foundation; grants from MSD; support for attending meetings from Gilead, MSD, ViiV, and Pfizer; and advisory board fees from Gilead, MSD, ViiV, Pfizer, Moderna, AstraZeneca, Abbvie, and Lilly. The institution of PS received honoraria for advisory board participation and support for attending meetings from ViiV and Gilead. None of those grants and supports was related to the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thoueille, Saldanha, Schaller, Choong, Veuve, Munting, Cavassini, Braun, Günthard, Duran Ramirez, Surial, Furrer, Rauch, Ustero, Calmy, Stöckle, Di Benedetto, Bernasconi, Schmid, Marzolini, Girardin, Buclin, Decosterd and Guidi.)

Background: Advancements in access to antiretroviral therapy (ART) and human immunodeficiency virus (HIV) care have led to a decline in AIDS-related deaths among people with HIV (PWH) in Switzerland. However, data on the ongoing changes in causes of death among PWH over the past 15 years are scarce., Methods: We investigated all reported deaths in the Swiss HIV Cohort Study between 2005 and 2022. Causes of death were categorized using the Coding Causes of Death in HIV protocol. The statistical analysis included demographic stratification to identify time trends and logistic regression models to determine associated factors for the underlying cause of death., Results: In total, 1630 deaths were reported, with 23.7% of individuals assigned female sex at birth. These deaths included 147 (9.0%) HIV/AIDS-related deaths, 373 (22.9%) due to non-AIDS, non-hepatic cancers, 166 (10.2%) liver-related deaths, and 158 (9.7%) cardiovascular-related deaths. The median age at death (interquartile range) increased from 45.0 (40.0-53.0) years in 2005-2007 to 61.0 (56.0-69.5) years in 2020-2022. HIV/AIDS- and liver-related deaths decreased, whereas deaths from non-AIDS, non-hepatic cancers increased and cardiovascular-related deaths remained relatively stable., Conclusions: The proportionally decreasing HIV/AIDS and liver-related deaths showcase the effectiveness of ART, comprehensive HIV patient care, and interventions targeting hepatitis C virus coinfection. Future research should focus on managing cancer and cardiovascular-related conditions as the new leading causes of death among PWH. Comprehensive healthcare strategies focusing on non-AIDS-related comorbid conditions, cancer management, and sustaining liver and cardiovascular health are needed to bridge the ongoing health disparities between PWH and the general population., Competing Interests: Potential conflicts of interest . M. S. R. W. has received conference travel grants from Gilead. J. J. D. R. has received educational research grants to their institution from Gilead Sciences and ViiV healthcare, unrelated to the present work. M. H. received travel grants from Gilead Science, ViiV Healthcare and MSD; lecture honoraria for conference report from Gilead Science and ViiV Healthcare; and payment for expert testimony from ViiV Healthcare and Gilead Science, all unrelated to the present work. M. C.'s institution received research grants from Gilead, MSD and ViiV healthcare; reports payment for expert testimony from MSD, Gilead, and ViiV; and travel grants from Gilead. E. B's institution received a research grant from MSD, fees for E. B.'s participation on advisory boards and/or travel grants from Gilead, ViiV, MSD, AbbVie, Pfizer, AstraZeneca, Moderna, and Ely Lilly; E. B. also reports consulting fees from Moderna and payment or honoraria from Pfizer. E. H. received financial support for attending meetings from Gilead Sciences, ViiV healthcare, and AstraZeneca; the travel grants were paid to her institution. H. F. received educational grants from ViiV, MSD, AbbVie, Gilead, Sandoz, AstraZeneca and Pfizer, paid to his institution. M. S. received money for advisory boards and/or travel grants from Gilead, ViiV, and MSD, paid to his institution, and reports an unpaid leadership or fiduciary role with the SHCS. P. S.'s institution has received travel grants, congress, and advisory fees from ViiV and Gilead, unrelated to the present work. D. H. has received consultancies from AstraZeneca, Gilead, ViiV Healthcare, and Bavarian Nordic, as well as institutional funding from AbbVie, AstraZeneca, Gilead, GSK, MSD, Pfizer, Roche, ViiV Healthcare; reports support for travel and/or attending meetings from Gilead; and reports leadership or fidicuary roles with Patient Focused Medicines Development (PFMD) and Positive Council Switzerland. D. L. B. reports honoraria for advisory boards or speaker lectures, paid to himself, from Gilead, MSD, Pfizer, and ViiV and support for attending meetings and/or travel from Gilead and ViiV, unrelated to the present work. H. F. G. has received honoraria for data and safety monitoring board or advisory board membership from Merck, Gilead Sciences, ViiV Healthcare, GSK, Janssen, Johnson & Johnson, and Novartis and a travel grant from Gilead Sciences. He also reports unrestricted research grants from Gilead Sciences; grants or contracts paid to his institution from the Swiss National Science Foundation, the SCHS, and the National Institutes of Health; and unrestricted research grants from Gilead sciences and the Yvonne Jacob Foundation. All other authors report no potential conflicts All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)