Safety and drug quantification of the dapivirine vaginal ring and oral pre-exposure prophylaxis in breastfeeding mother-infant pairs (MTN-043): a phase 3B, open-label, randomised trial.

IF 12.8 1区 医学 Q1 IMMUNOLOGY
Lancet Hiv Pub Date : 2025-03-01 Epub Date: 2025-02-12 DOI:10.1016/S2352-3018(24)00306-0
Lisa M Noguchi, Maxensia Owor, Nyaradzo M Mgodi, Brenda Gati Mirembe, Sufia Dadabhai, Elizea Horne, Holly Gundacker, Barbra A Richardson, Katherine Bunge, Rachel Scheckter, Mei Song, Mark A Marzinke, Peter L Anderson, Edward Livant, Cindy Jacobson, Jeanna M Piper, Nahida Chakhtoura, Sharon L Hillier, Jennifer E Balkus
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引用次数: 0

Abstract

Background: In 2021, WHO recommended dapivirine vaginal rings (DVRs) for HIV prevention, but noted evidence gaps for breastfeeding populations. This trial aimed to describe safety profiles associated with DVRs and oral pre-exposure prophylaxis (PrEP) use during breastfeeding and to summarise study-drug quantification and concentrations for mothers and infants.

Methods: Microbicide Trials Network (MTN)-043 was a phase 3b, open-label, randomised trial in which mother-infant pairs were recruited from local health facilities and enrolled at four HIV clinical trial sites in Malawi, South Africa, Uganda, and Zimbabwe. Eligible mothers (aged ≥18 years) were HIV-negative, exclusively breastfeeding one infant (aged 6-12 weeks, birthweight ≥2000 g), and had not been exposed to HIV post-exposure prophylaxis in the previous 6 months. Mother-infant pairs were randomly assigned (3:1) via a computer-generated sequence to 12 weeks of 25 mg monthly DVR or daily oral PrEP (200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate), with stratification by site using a permuted block design. Participants and staff were aware of study product assignment. Primary outcomes were maternal and infant safety (all serious adverse events and grade 3 or worse adverse events) and drug concentrations, which were measured in maternal plasma, maternal blood, breastmilk, infant plasma, and infant blood. All mother-infant pairs who received at least one dose of study product were included in the primary safety analysis, and those with at least one post-enrolment drug concentration result were included in the drug quantification analysis. The trial was registered at ClinicalTrials.gov (NCT04140266).

Findings: Between Sept 24, 2020, and July 29, 2021, 197 mother-infant pairs enrolled (148 on DVR and 49 on PrEP), all of whom received at least one dose of study product and were included in the primary safety analysis. Two (1%) of 148 mothers in the DVR group had serious adverse events, and three (2%) in the DVR group and two (4%) in the oral PrEP group had a grade 3 or worse adverse event; four (3%) of 148 infants in the DVR group had a serious adverse event, and ten (7%) in the DVR group and one (2%) in the oral PrEP group had a grade 3 or worse adverse event. No mother or infant in the oral PrEP group had a serious adverse event. No HIV infections were detected. 144 participants in the DVR group and 48 in the oral PrEP group had at least one post-enrolment drug concentration result. Quantifiable median dapivirine concentrations ranged from 656·0 (IQR 407·0-878·0) pg/mL at week 1 to 558·5 (282·0-778·0) pg/mL at month 3, but were observed infrequently (5-15%) in specimens from infants, with median concentrations below the limit of quantification at all visits. Median tenofovir diphosphate concentrations ranged from 263·0 (193·0-363·0) fmol/punch at week 1 to 777·0 (381·0-1241·0) fmol/punch at month 3, but were not observed in specimens from infants, with all concentrations below the limit of quantification at all visits.

Interpretation: Increased risk of HIV acquisition in the postnatal period, favourable product safety profile, and low drug exposures among infants support the recommendation for DVRs as an additional HIV prevention choice during breastfeeding.

Funding: US National Institutes of Health.

达匹韦林阴道环和口服暴露前预防剂对哺乳母婴的安全性和药物定量(MTN-043):一项 3B 期、开放标签、随机试验。
背景:2021年,世卫组织推荐使用达匹韦林阴道环预防艾滋病毒,但注意到母乳喂养人群的证据差距。该试验旨在描述母乳喂养期间dvr和口服暴露前预防(PrEP)使用相关的安全性概况,并总结研究药物的定量和母婴浓度。方法:杀微生物剂试验网络(MTN)-043是一项3b期、开放标签、随机试验,在马拉维、南非、乌干达和津巴布韦的四个HIV临床试验点招募了来自当地卫生机构的母婴对。符合条件的母亲(年龄≥18岁)为艾滋病毒阴性,纯母乳喂养一名婴儿(6-12周,出生体重≥2000 g),并且在过去6个月内未接受过艾滋病毒暴露后预防。通过计算机生成的序列,将母婴对随机分配(3:1)至12周,每月25mg DVR或每日口服PrEP (200 mg恩曲他滨和300 mg富马酸替诺福韦二吡酯),采用排列块设计按部位分层。参与者和工作人员都知道研究产品分配。主要结局是母婴安全性(所有严重不良事件和3级或更严重的不良事件)和药物浓度,分别在母体血浆、母体血液、母乳、婴儿血浆和婴儿血液中测量。所有接受了至少一剂研究产品的母婴对被纳入初级安全性分析,至少有一种入组后药物浓度结果的母婴被纳入药物定量分析。该试验已在ClinicalTrials.gov注册(NCT04140266)。研究结果:在2020年9月24日至2021年7月29日期间,纳入了197对母婴(148对使用DVR, 49对使用PrEP),所有人都接受了至少一剂研究产品,并被纳入主要安全性分析。DVR组148名母亲中有2名(1%)出现严重不良事件,DVR组3名(2%)和口服PrEP组2名(4%)出现3级或更严重的不良事件;DVR组148名婴儿中有4名(3%)发生严重不良事件,DVR组10名(7%)和口服PrEP组1名(2%)发生3级或更严重的不良事件。口服PrEP组中没有母亲或婴儿出现严重不良事件。没有发现艾滋病毒感染。DVR组144名受试者和口服PrEP组48名受试者至少有一项入组后药物浓度结果。可量化的中位浓度范围为第1周时的656·0 (IQR 407·0-878·0)pg/mL至第3个月时的5558·5 (IQR 282·0-778·0)pg/mL,但在婴儿标本中观察到的中位浓度很少(5-15%),在所有访问中均低于定量极限。替诺福韦二磷酸的中位浓度从第1周的263·0(193·0-363·0)fmol/punch到第3个月的777·0(381·0-1241·0)fmol/punch不等,但在婴儿标本中未观察到,所有访问时的浓度均低于定量限制。解释:产后艾滋病毒感染风险增加,产品安全性良好,婴儿药物暴露率低,支持将dvr作为母乳喂养期间预防艾滋病毒的额外选择的建议。资助:美国国立卫生研究院。
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来源期刊
Lancet Hiv
Lancet Hiv IMMUNOLOGYINFECTIOUS DISEASES&-INFECTIOUS DISEASES
CiteScore
19.90
自引率
4.30%
发文量
368
期刊介绍: The Lancet HIV is an internationally trusted source of clinical, public health, and global health knowledge with an Impact Factor of 16.1. It is dedicated to publishing original research, evidence-based reviews, and insightful features that advocate for change in or illuminates HIV clinical practice. The journal aims to provide a holistic view of the pandemic, covering clinical, epidemiological, and operational disciplines. It publishes content on innovative treatments and the biological research behind them, novel methods of service delivery, and new approaches to confronting HIV/AIDS worldwide. The Lancet HIV publishes various types of content including articles, reviews, comments, correspondences, and viewpoints. It also publishes series that aim to shape and drive positive change in clinical practice and health policy in areas of need in HIV. The journal is indexed by several abstracting and indexing services, including Crossref, Embase, Essential Science Indicators, MEDLINE, PubMed, SCIE and Scopus.
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