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AimTo characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability.MethodsAnalyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P

Background: Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants., Methods: Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination)., Results: Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses., Conclusions: The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA., Competing Interests: Potential conflicts of interest . C. O. reports personal fees and grants from ViiV Healthcare, GSK, Gilead Sciences, MSD, and Janssen; grants from AstraZeneca; travel support from Gilead Sciences and ViiV Healthcare; and is the president of the Medical Women's Federation (UK) and a governing council member of the International AIDS Society. J. M. S. reports personal consulting fees, honoraria, travel support, participation on a Data Safety Monitoring or Advisory Board, and nonfinancial support from Gilead Sciences, Merck, ViiV Healthcare, Pfizer, Moderna, GSK, Teva, and AbbVie. C. F. P. reports consulting fees and payment or honoraria from Gilead Sciences, ViiV Healthcare, GSK, AstraZeneca, Janssen, and Merck; and participation on a Data Safety Monitoring or Advisory Board for ViiV Healthcare, Gilead Sciences, Merck, and Janssen. D. R. K. has received grants from ViiV Healthcare, Gilead Sciences, Merck, and the National Institutes of Health; reports payment for expert testimony from Gilead Sciences; consulting fees from Gilead Sciences, GSK, Janssen, AbbVie, Merck, and ViiV Healthcare; payment or honoraria from Gilead Sciences and Janssen; and participation on a Data Safety Monitoring or Advisory Board for GSK and ViiV Healthcare. P. P., Y. W., C. L. L., M. S. C., J. W. P., R. D’A., H. P. G., A. Z., W. R. S., J. v. W., and A. G. C. are employees of ViiV Healthcare and stockholders of GSK. R. D., D. D., K. H., and S. L. F. are employees and stockholders of GSK. H. C., S. V., and K. V. are employees and may be stockholders of Janssen, Pharmaceutical Companies of Johnson & Johnson. V. V. E. is an employee and may be a stockholder of Janssen, Pharmaceutical Companies of Johnson & Johnson, and has a pending patent for HIV infection treatment in children., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged., Methods: We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years)., Findings: Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years)., Interpretations: In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.