Evaluation of long-acting cabotegravir safety and pharmacokinetics in pregnant women in eastern and southern Africa: a secondary analysis of HPTN 084

IF 4.6 1区医学 Q2 IMMUNOLOGY

Journal of the International AIDS Society Pub Date : 2025-01-02 DOI:10.1002/jia2.26401

Sinead Delany-Moretlwe, Brett Hanscom, Xu Guo, Clemensia Nkabiito, Patricia Mandima, Patricia Ntege Nahirya, Juliet Mpendo, Muchaneta Bhondai-Mhuri, Nyaradzo Mgodi, Rebecca Berhanu, Jennifer Farrior, Estelle Piwowar-Manning, Susan L. Ford, Craig W. Hendrix, Alex R. Rinehart, James F. Rooney, Adeola Adeyeye, Raphael J. Landovitz, Myron S. Cohen, Mina C. Hosseinipour, Mark A. Marzinke, the HPTN 084 Study Team

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Abstract

Introduction

Long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB-LA pharmacokinetics in pregnant women during the blinded period of HPTN 084.

Methods

Participants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open-label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth ≥20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half-life (t_1/2app) of CAB-LA in pregnant women in HPTN 084 was compared to non-pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t_1/2app.

Results

Fifty-seven pregnancies (30 CAB-LA, 27 TDF/FTC) were confirmed over 3845 person-years [py] (incidence 1.5/100 py, 95% CI 1.1−1.9). CAB-LA group participants had a median 342 days (IQR 192, 497) of CAB-LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91−271 per 100 py vs. TDF/FTC 217, 95% CI 124–380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB-LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t_1/2app geometric mean was 52.8 days (95% CI 40.7−68.4) in pregnant women compared to 60.3 days (95% CI 47.7−76.3; p = 0.66) in non-pregnant women; neither pregnancy nor body mass index were significantly associated with t_1/2app.

Conclusions

CAB-LA concentrations post-cessation of injections were generally well tolerated in pregnant women. The t_1/2app was comparable between pregnant and non-pregnant women. Ongoing studies will examine the safety and pharmacology of CAB-LA in women who choose to continue CAB-LA through pregnancy and lactation.

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非洲东部和南部孕妇长效卡布特韦安全性和药代动力学评价：HPTN 084的二次分析

简介在 HPTN 084 中，用于暴露前预防的长效注射卡博替拉韦（CAB-LA）显著降低了 HIV 感染率。我们报告了 HPTN 084 盲法期间孕妇使用 CAB-LA 的安全性和药代动力学：参与者按 1:1 随机分配到活性卡博特拉韦 (CAB) 加替诺福韦二吡呋酯/恩曲他滨（TDF/FTC）安慰剂或活性 TDF/FTC 加 CAB 安慰剂。每次就诊时都进行妊娠检测；检测结果呈阳性的受试者将被扣留研究产品，并接受开放标签 TDF/FTC。两次检测至少间隔 4 周才能确认是否怀孕。所有在 2020 年 11 月 5 日之前妊娠检测呈阳性的参与者均纳入本次分析。HPTN 084试验中孕妇的妊娠发生率、母体不良事件（AE）发生率、CAB-LA的妊娠结局（包括自然流产1/2app的复合结局）与2a期HPTN 077试验中的非孕妇进行了比较。多变量模型评估了与 t1/2app 的关联。结果：在3845人/年[py]的时间里，确认了57例妊娠（30例CAB-LA，27例TDF/FTC）（发生率为1.5/100 py，95% CI为1.1-1.9）。CAB-LA 组参与者在检测到妊娠之前的 CAB-LA 暴露时间中位数为 342 天（IQR 192，497）。不同研究臂的 2 级或以上孕产妇 AE 发生率没有差异（CAB 157，95% CI 91-271 per 100 py vs. TDF/FTC 217，95% CI 124-380 per 100 py; p = 0.256）。大多数妊娠（81%）均为活产（25 例 CAB-LA，22 例 TDF/FTC）。各组的综合不良妊娠结局无显著差异（CAB 6/30 vs. TDF/FTC 4/27; p = 0.476）。未观察到先天性畸形。孕妇的 CAB t1/2app 几何平均数为 52.8 天（95% CI 40.7-68.4），而非孕妇为 60.3 天（95% CI 47.7-76.3；p = 0.66）；妊娠和体重指数均与 t1/2app 无显著相关性：结论：孕妇对停止注射后 CAB-LA 浓度的耐受性普遍良好。孕妇和非孕妇的 t1/2app 值相当。正在进行的研究将对选择在妊娠期和哺乳期继续使用 CAB-LA 的妇女进行 CAB-LA 的安全性和药理学研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of the International AIDS Society IMMUNOLOGY-INFECTIOUS DISEASES

CiteScore

8.60

自引率

10.00%

发文量

186

审稿时长

>12 weeks

期刊介绍： The Journal of the International AIDS Society (JIAS) is a peer-reviewed and Open Access journal for the generation and dissemination of evidence from a wide range of disciplines: basic and biomedical sciences; behavioural sciences; epidemiology; clinical sciences; health economics and health policy; operations research and implementation sciences; and social sciences and humanities. Submission of HIV research carried out in low- and middle-income countries is strongly encouraged.