Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial
| Autor: | Sue Li, Craig W. Hendrix, Joseph J. Eron, Albert Y. Liu, Mark A. Marzinke, Paul G. Richardson, Alex R. Rinehart, Marybeth McCauley, Adeola Adeyeye, Susan H. Eshleman, Gordon Chau, Manya Magnus, Beatriz Grinsztejn, Ravindre Panchia, Raphael J. Landovitz, David N. Burns, Halima Dawood, Ryan Kofron, Myron S. Cohen, Leslie Cottle, David Margolis, Mina C. Hosseinipour |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Malawi medicine.medical_specialty Anti-HIV Agents Pyridones Epidemiology Immunology HIV Infections Placebo Injections law.invention Cohort Studies Placebos South Africa Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cabotegravir Double-Blind Method Randomized controlled trial Pharmacokinetics law Virology Internal medicine medicine Humans HIV Integrase Inhibitors 030212 general & internal medicine Adverse effect business.industry Incidence (epidemiology) Middle Aged 030112 virology United States Infectious Diseases chemistry Cohort Female business Brazil Cohort study |
| Zdroj: | The Lancet HIV. 7:e472-e481 |
| ISSN: | 2352-3018 |
| DOI: | 10.1016/s2352-3018(20)30106-5 |
| Popis: | Summary Background Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. Methods HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18–65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52–76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov , NCT02178800 . Findings Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p Interpretation The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. Funding National Institute of Allergy and Infectious Diseases. |
| Databáze: | OpenAIRE |
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