利比韦林
医学
药代动力学
药理学
人类免疫缺陷病毒(HIV)
安全概况
不利影响
病毒学
抗逆转录病毒疗法
病毒载量
作者
Aditya H. Gaur,Edmund V. Capparelli,Katherine Calabrese,Kristin Baltrusaitis,Mark A. Marzinke,Cynthia McCoig,Rodica M. Van Solingen-Ristea,Sisinyana Ruth Mathiba,Adeola Adeyeye,John Moye,Barbara Heckman,Elizabeth Lowenthal,S. M. Ward,Ryan O. Milligan,Pearl Samson,Brookie M. Best,Conn M Harrington,Susan L. Ford,Jenny Huang,Herta Crauwels,Kati Vandermeulen,Allison L. Agwu,Christiana Smith-Anderson,Andrés Camacho-González,Pradthana Ounchanum,Jared L Kneebone,Ellen Townley,Carolyn Bolton‐Moore,Sarah Buisson,S.Y. Amy Cheung,Vasiliki Chounta,Isabelle Déprez,Alicia Catherine Desmond,Kelong Han,Sherika Hanley,Yu-Wei Lin,Faeezah Patel,Mary E. Paul,Gilly Roberts,Kyle Whitson,Sara Zabih
标识
DOI:10.1016/s2352-3018(23)00300-4
摘要
Summary
Background
Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents. Methods
In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12–17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4–6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0–tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2–4 after oral dosing and weeks 4–16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment. Findings
Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82–100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72–99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0–22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0–tau was 148·5 (range 37·2–433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22–6·19) and 1·15 μg/mL (<0·025–5·29) for cabotegravir and 52·9 ng/mL (31·9–148·0) and 39·1 ng/mL (27·2–81·3) for rilpivirine, respectively. These concentrations were similar to those in adults. Interpretation
Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg. Funding
The National Institutes of Health and ViiV Healthcare.